Ring fused pyrazole derivatives as CRF antagonists

ABSTRACT

This invention relates to compounds which are generally CRF-1 receptor antagonists and which are represented by Formula I or Formula II:  
                 
 
     wherein Ar is optionally substituted aryl or heteroaryl, R 1 -R 4  are as defined in the specification; or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts thereof. The invention further relates to processes for preparing such compounds, to pharmaceutical compositions containing such compounds, and to methods for their use as therapeutic agents.

CROSS REFERENCE TO PRIOR APPLICATIONS

[0001] This application claims benefit under Title 35 U.S.C. 119(e) ofU.S. Provisional Applications No. 60/336,751 filed Dec. 4, 2001; and No.60/408,613 filed Sep. 6, 2002, all applications are hereby incorporatedby reference in its entirety.

FIELD OF THE INVENTION

[0002] This invention relates to ring fused pyrazole derivatives withCRF activity, and associated pharmaceutical compositions, and methodsfor use as therapeutic agents.

BACKGROUND OF THE INVENTION

[0003] Corticotropin releasing factor (CRF) or hormone (CRH) is one ofseveral neurohormones synthesized by specific hypothalamic nuclei in thebrain where it activates the transcription of the pro-opiomelanocortin(POMC) gene resulting in release of adrenocorticotropic hormone (ACTH)and beta-endorphin from anterior pituitary cells (Vale et al, Science213,1394-1397 (1981)). The fundamental role of CRF is to prepare theorganism for an appropriate response to various stressors such asphysical trauma, insults of the immune system and social interactions.CRF also has CNS effects by acting at higher centers in the brain,particularly cortical regions where there is a widespread distributionof CRF neurons. CRF is believed to be a key intermediary incommunication between the immune, central nervous, endocrine andcardiovascular systems (Sapolsky et al, Science 238, 522-524 (1987)).The role played by CRF in integrating the response of the immune systemto physiological, psychological and immunological stressors has beendescribed in the art, e.g. J. E. Blalock, Physiological Reviews 69,1(1989) and J. E. Morley, Life Sci. 41, 527 (1987).

[0004] CRF antagonists are effective in the treatment of a wide range ofstress-related illnesses, mood disorders such as depression, majordepressive disorder, single episode depression, recurrent depression,child abuse induced depression, postpartum depression, dysthemia,bipolar disorder and cyclothymia; chronic fatigue syndrome; eatingdisorders such as obesity, anorexia and bulimia nervosa; generalizedanxiety disorder; panic disorder; phobias; obsessive-compulsivedisorder; post-traumatic stress disorder; pain perception such asfibromyalgia; headache; stress-induced gastrointestinal dysfunction suchas irritable bowel syndrome (IBS), colonic hypersensitivity or spasticcolon; hemorrhagic stress; ulcers; stress-induced psychotic episodes;inflammatory disorders such as rheumatoid arthritis and osteoarthritis;asthma; psoriasis; allergies; premature birth; hypertension; congestiveheart failure; sleep disorders; neurodegenerative diseases such asAlzheimer's disease, senile dementia, Parkinson's disease andHuntington's disease; head or spinal cord trauma; ischemic neuronaldamage; excitotoxic neuronal damage; epilepsy; stroke; psychosocialdwarfism; chemical dependencies and addictions; drug and alcoholwithdrawal symptoms; stress-induced immune dysfunctions; immunesuppression and stress-induced infections; cardiovascular or heartrelated diseases; fertility problems; and/or human immunodeficiencyvirus infections. Accordingly clinical data suggests that CRF receptorantagonists may represent novel antidepressants and/or anxiolytic drugsthat may be useful in the treatment of the neuropsychiatric disordersmanifesting hypersecretion of CRF.

[0005] In view of the above, efficacious and specific antagonists of CRFare desired as potentially valuable therapeutic agents for the treatmentof psychiatric disorders and neurological diseases. It is thus desirableto discover new CRF antagonists.

[0006] All publications, patents, and patent applications cited herein,whether supra or infra, are each hereby incorporated by reference in itsentirety.

SUMMARY OF THE INVENTION

[0007] This invention relates to compounds comprising Formula I orFormula II:

[0008] wherein:

[0009] R¹ is —OR^(a), —NR^(a)R^(b), —CR^(c)R^(d)R^(e), CO₂R^(a), or—C(O)NR^(a)R^(b); or R¹ is hydrogen, halogen, cycloalkenyl, aryl, orheteroaryl, where each aryl or heteroaryl is optionally substituted withone or more substituents independently selected from C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, halogen, haloalkyl, cyano,nitro, —C(O)NR^(a′)R^(b′), and —NR^(a′)R^(b′), where R^(a′) and R^(b′)are each independently selected from the group consisting of hydrogen,C₁₋₉alkyl, and C₁₋₉alkylcarbonyl;

[0010] R² is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl,C₁₋₆alkylcarbonyl, C₁₋₆alkylsulfonyl, aryl, or arylalkyl, wherein saidaryl or arylalkyl is optionally substituted with one or moresubstituents independently selected from C₁₋₆alkyl, haloalkyl,C₁₋₆alkoxy, and halogen;

[0011] R³ and R⁴ are each independently selected from hydrogen andC₁₋₆alkyl, or R³ and R⁴ are taken together with the carbon to which theyare attached to form a C₃₋₆cycloalkyl ring;

[0012] Ar is aryl or heteroaryl, each optionally substituted with one ormore substituents independently selected from the group consisting ofC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl;

[0013] R^(a) and R^(b) are each independently selected from the groupconsisting of hydrogen, C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,C₁₋₆alkylthioalkyl, carboxyalkyl, C₁₋₆ alkoxycarbonyl, C₁₋₆-alkoxy-C₁₋₃alkylcarbonyl, acyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl,di-C₃₋₆cycloalkylC₁₋₃alkyl, C₁₋₆heteroalkyl, aminoalkyl,aminocarbonylalkyl, cyanoalkyl, C₅₋₈heterocyclyl, heterocyclylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, phenylalkyl,diphenylalkyl, phenylsulfonyl optionally substituted as described forphenyl below, and C₁₋₃alkyl substituted with both a C₃₋₆cycloalkyl and aphenyl group, wherein each of said cycloalkyl, phenyl, aryl, orheteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, andhalogen, and each of said amino groups is optionally monosubstituted ordisubstituted with alkyl; or

[0014] R^(a) and R^(b) are taken together with the nitrogen to whichthey are attached form an heterocyclyl or heteroaryl ring selected fromthe group consisting of pyrrolidine, piperidine, homopiperidine,tetrahydropyridine, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine,hexahydropyrimidine, pyrazolidine, piperazine, morpholine, imidazoline,pyrrole, pyrazole, and imidazole, where each of said rings is optionallysubstituted with one or more substituents selected from the groupconsisting of hydroxy, oxo, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl,aminoalkyl, acyl, acylamino, aminocarbonyl, aminocarbonylalkyl,aminocarbonylamino, aminosulfonyl, alkylsulfonylamino,aminosulfonylamino, and phenyl, wherein each of said phenyl groups isoptionally substituted with one or more groups independently selectedfrom C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,and halogen, and each of said amino groups is optionally monosubstitutedor disubstituted with alkyl, or is contained in a pyrrolidinyl,piperidinyl, morpholinyl, or piperazinyl group;

[0015] R^(c) is hydrogen, hydroxy, C₁₋₆alkoxy, or —NR^(a′″)R^(b′″);

[0016] R^(d) and R^(e) are each independently selected from the groupconsisting of hydrogen, C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,C₁₋₆alkylthioalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl, di-C₃₋₆cycloalkyl-C₁₋₃alkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, phenylalkyl, diphenyl-C₁₋₃alkyl,and C₁₋₃alkyl substituted with both a C₃₋₆cycloalkyl and a phenyl group,wherein each of said cycloalkyl, phenyl, aryl, or heteroaryl groups isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy,amino, alkylamino, dialkylamino, and halogen; or

[0017] R^(c) and R^(d) are taken together to form a divalent groupselected from C₁₋₆alkylidenyl, C₁₋₆heteroalkylidenyl,C₃₋₆cycloalkylidenyl, C₃₋₆cycloalkyl-alkylidenyl,C₃₋₆cycloalkylalkyl-alkylidenyl, C₃₋₆heterocyclylidenyl,C₃₋₆heterocyclyl-C₁₋₃alkylidenyl, C₃₋₆heterocyclylalkyl-C₁₋₃alkylidenyl,aryl-C₁₋₃alkylidenyl, aryl-C₁₋₃alkyl-alkylidenyl,heteroaryl-C₁₋₃alkylidenyl, and heteroarylalkyl-C₁₋₃alkylidenyl, whereineach of said cycloalkyl, aryl, or heteroaryl groups is optionallysubstituted with one or more substituents independently selected fromC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino, andhalogen; or

[0018] R^(d) and R^(e) are taken together with the carbon to which theyare attached to form a cycloalkyl or heterocyclyl ring;

[0019] R^(a′″) and R^(b′″) are each independently selected from thegroup consisting of hydrogen, C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,C₁₋₆alkylthioalkyl, carboxyalkyl, Cl-6 alkoxycarbonyl, C₁₋₆-alkoxy-C₁₋₃alkylcarbonyl, acyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl,di-C₃₋₆cycloalkyl-C₁₋₃alkyl, C₁₋₆heteroalkyl, aminoalkyl,aminocarbonylalkyl, cyanoalkyl, C₅₋₈heterocyclyl, heterocyclylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, phenylalkyl,diphenyl-C₁₋₃alkyl, and C₁₋₃alkyl substituted with both a C₃₋₆cycloalkyland a phenyl group, wherein each of said cycloalkyl, phenyl, aryl, orheteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, andhalogen, and each of said amino groups is optionally monosubstituted ordisubstituted with alkyl; or

[0020] R^(a′″) and R^(b′″) are taken together with the nitrogen to whichthey are attached form an heterocyclyl or heteroaryl ring selected fromthe group consisting of pyrrolidine, piperidine, homopiperidine,tetrahydropyridine, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine,hexahydropyrimidine, pyrazolidine, piperazine, morpholine, imidazoline,pyrrole, pyrazole, and imidazole, where each of said rings is optionallysubstituted with one or more substituents selected from the groupconsisting of hydroxy, oxo, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl,aminoalkyl, acyl, acylamino, aminocarbonyl, aminocarbonylalkyl,aminocarbonylamino, aminosulfonyl, alkylsulfonylamino,aminosulfonylamino, and phenyl, wherein each of said phenyl groups isoptionally substituted with one or more groups independently selectedfrom C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,and halogen, and each of said amino groups is optionally monosubstitutedor disubstituted with alkyl, or is contained in a pyrrolidinyl,piperidinyl, morpholinyl, or piperazinyl group;

[0021] n is an integer selected from 0, 1 and 2;

[0022] a is a single or double bond;

[0023] providing that when n is 0, R¹ is not hydrogen; when n is 0 and ais a double bond, R⁴ is absent; and when n is 1 or 2, a is a singlebond;

[0024] or individual isomers, racemic or non-racemic mixtures ofisomers, or pharmaceutically acceptable salts or solvates thereof.

[0025] In one embodiment, a compound of Formula I is described:

[0026] wherein R¹, R², R³, R⁴, Ar, a, and n are as defined above.

[0027] In another embodiment, compounds of Formula III are described:

[0028] wherein the integer n is 1 or 2, and R¹, R², R³, R⁴, and Ar areas defined above.

[0029] In another embodiment, compounds of Formula III are described,wherein Ar is a di- or tri-substituted phenyl, and the substituents areeach independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, and R¹, R², R³, and R⁴are as defined above.

[0030] In one aspect, such compounds are described wherein R³ and R⁴ areeach independently selected from hydrogen and methyl.

[0031] In another aspect, such compounds are described wherein Ar is a2,4-disubstituted or 2,4,6-trisubstituted phenyl, and the substituentsare each independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl.

[0032] In another aspect, such compounds are described wherein Ar is a2,4-disubstituted or 2,4,6-trisubstituted phenyl, and the substituentsare each independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, halogen, haloalkyl, cyano, alkylamino,dialkylamino, and nitro.

[0033] In another aspect, such compounds are described wherein R² ishydrogen, C₁₋₆alkyl, or C₁₋₆alkylcarbonyl.

[0034] In another embodiment, compounds of Formula IV are described:

[0035] wherein Ar is a 2,4-disubstituted or 2,4,6-trisubstituted phenyl,and the substituents are each independently selected from the groupconsisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio, halogen, haloalkyl,cyano, alkylamino, dialkylamino, and nitro, R² is hydrogen, C₁₋₆alkyl,or C₁₋₆alkylcarbonyl, R³ and R⁴ are each independently selected fromhydrogen and methyl; and R¹ is as defined above.

[0036] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted phenyl, and the substituents areeach independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

[0037] R¹ is —CR^(c)R^(d)R^(e); R^(c) is hydroxy; and R^(d) and R^(e)are as defined above.

[0038] In one aspect, such compounds are described wherein R^(d) andR^(e) are each independently selected from the group consisting ofhydrogen, C₁₋₉alkyl, C₁₋₆alkoxyalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl,where each of said aryl or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen.

[0039] In one alternative, such compounds are described wherein R^(d)and R^(e) are each independently selected from the group consisting ofC₁-alkyl, C₁₋₆alkoxyalkyl, aryl, and heteroaryl, where each of said arylor heteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen.

[0040] In another aspect, such compounds are described wherein R² isC₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar is a 2,4-disubstituted or2,4,6-trisubstituted phenyl, and the substituents are each independentlyselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen,haloalkyl, cyano, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen andC₁₋₉alkyl.

[0041] In another alternative, such compounds are described whereinR^(d) and R^(e) are taken together to form a cycloalkyl or heterocyclylgroup.

[0042] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted phenyl, and the substituents areeach independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

[0043] R¹ is —CR^(c)R^(d)R^(e); R^(e) is selected from the groupconsisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl,where each of said aryl or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen; and R^(c)and R^(d) are taken together to form a divalent group selected fromC₁₋₆alkylidenyl, C₁₋₆heteroalkylidenyl, C₃₋₆cycloalkylidenyl,C₃₋₆cycloalkyl-alkylidenyl, C₃₋₆cycloalkylalkyl-alkylidenyl,C₃₋₆heterocyclylidenyl, C₃₋₆heterocyclyl-C₁₋₃alkylidenyl,C₃₋₆heterocyclylalkyl-C₁₋₃alkylidenyl, aryl-C₁₋₃alkylidenyl,aryl-C₁₋₃alkyl-alkylidenyl, heteroaryl-C₁₋₃alkylidenyl, andheteroarylalkyl-C₁₋₃alkylidenyl, wherein each of said cycloalkyl, aryl,or heteroaryl groups is optionally substituted with one or moresubstituents independently selected from C₁₋₆alkyl, haloalkyl,C₁₋₆alkoxy, amino, alkylamino, dialkylamino, and halogen.

[0044] In one alternative, such compounds are described wherein R^(c)and R^(d) are taken together to form a divalent group selected fromC₁₋₆alkylidenyl, C₃₋₆cycloalkyl-alkylidenyl, aryl-C₁₋₃alkylidenyl, andheteroaryl-C₁₋₃alkylidenyl, wherein each of said aryl or heteroarylgroups is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino,alkylamino, dialkylamino, and halogen.

[0045] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted phenyl, and the substituents areeach independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

[0046] R¹ is —CR^(c)R^(d)R^(e); R^(e) is selected from the groupconsisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl, and heteroaryl, where theheteroaryl is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆alkyl,haloalkyl, C₁₋₆alkoxy, and halogen; and R^(c) and R^(d) are takentogether to form a divalent group selected from C₁₋₆alkylidenyl,C₃₋₆cycloalkyl-alkylidenyl, C₃₋₆heterocyclyl-C₁₋₃alkylidenyl,aryl-C₁₋₃alkylidenyl, and heteroaryl-C₁₋₃alkylidenyl, wherein each ofsaid aryl, or heteroaryl groups is optionally substituted with one ormore substituents independently selected from C₁₋₆alkyl, C₁₋₆alkoxy,amino, alkylamino, and dialkylamino.

[0047] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted phenyl, and the substituents areeach independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

[0048] R¹ is —CR^(c)R^(d)R^(e); R^(c) is hydrogen; and R^(d) and R^(e)are as defined above.

[0049] In one aspect, such compounds are described wherein R^(d) andR^(e) are each independently selected from the group consisting ofC₁₋₉alkyl, C₁₋₆alkoxyalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl, where each of said aryl orheteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen.

[0050] In one alternative, such compounds are described wherein R^(d)and R^(e) are each independently selected from the group consisting ofC₁₋₉alkyl, C₁₋₆alkoxyalkyl, aryl, and heteroaryl, where each of saidaryl or heteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen; R² is C₁₋₆alkyl; R³ andR⁴ are hydrogen; and Ar is a 2,4-disubstituted or 2,4,6-trisubstitutedphenyl, and the substituents are independently selected from the groupconsisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl, cyano, and—NR^(a″)R^(b″), where R^(a″) and R^(b″) are each independently selectedfrom the group consisting of hydrogen and C₁₋₉alkyl.

[0051] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted phenyl, and the substituents areeach independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₆alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

[0052] R¹ is —NR^(a)Rb; —C(O)NR^(a)R^(b); or —CR^(c)R^(d)R^(e), whereR^(c) is —NR^(a′″)R^(b′″); R^(d) and R^(e) are each independentlyselected from the group consisting of hydrogen and C₁₋₉alkyl; and R^(a),R^(b), R^(a′″), and R^(b′″) are as defined above.

[0053] In one aspect, such compounds are described wherein R^(a), R^(b),R^(a), and R^(b) are each independently selected from the groupconsisting of hydrogen, C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,C₃₋₆cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl,wherein each of said aryl or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino,dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl,alkylsulfonyloxy, and halogen, and each of said amino groups isoptionally monosubstituted or disubstituted with alkyl.

[0054] In one alternative, such compounds are described wherein R^(a)and R^(b), or R^(a′″) and R^(b′″), are taken together with the nitrogento which they are attached form an heterocyclyl ring selected from thegroup consisting of pyrrolidine, piperidine, homopiperidine,tetrahydropyridine, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine,hexahydropyrimidine, pyrazolidine, piperazine, morpholine, andimidazoline, where each of said rings is optionally substituted with oneor more substituents independently selected from the group consisting ofhydroxy, oxo, alkyl, aminoalkyl, acyl, acylamino, aminocarbonyl,aminocarbonylalkyl, and aminocarbonylamino, and each of said aminogroups is optionally monosubstituted or disubstituted with alkyl, or iscontained in a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinylgroup.

[0055] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted phenyl, and the substituents areeach independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

[0056] R¹ is —NR^(a)R^(b); R^(a) is selected from the group consistingof hydrogen, C₁₋₉alkyl, and C₁₋₆alkoxyalkyl; and R^(b) is selected fromthe group consisting of C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,heterocyclylalkyl, arylalkyl, and heteroarylalkyl, wherein each of saidaryl or heteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, andhalogen, and each of said amino groups is optionally monosubstituted ordisubstituted with alkyl.

[0057] In one aspect, such compounds are described wherein R² isC₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar is a 2,4-disubstituted or2,4,6-trisubstituted phenyl, and the substituents are independentlyselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen,haloalkyl, cyano, and —NR^(a″)R^(b″), where R^(″) and R^(b″) are eachindependently selected from the group consisting of hydrogen andC₁₋₉alkyl.

[0058] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted phenyl, and the substituents areeach independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(″) and R^(b″) are each independentlyselected from the group consisting of hydrogen, C₁₋₉alkyl, andC₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above; and

[0059] R¹ is CR^(c)R^(d)R^(e); R^(c) is NR^(a′″)R^(b′″); R^(d) and R^(e)are each independently selected from the group consisting of hydrogenand C₁₋₉alkyl; R^(a′″) is selected from the group consisting ofhydrogen, C₁₋₉alkyl, and C₁₋₆alkoxyalkyl; and R^(b′″) is selected fromthe group consisting of C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,heterocyclylalkyl, arylalkyl, and heteroarylalkyl, wherein each of saidaryl or heteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, andhalogen, and each of said amino groups is optionally monosubstituted ordisubstituted with alkyl.

[0060] In one aspect, such compounds are described wherein R² isC₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar is a 2,4-disubstituted or2,4,6-trisubstituted phenyl, and the substituents are independentlyselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen,haloalkyl, cyano, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen andC₁₋₉alkyl.

[0061] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted phenyl, and the substituents areeach independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) 0 are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

[0062] R¹ is —OR^(a), and R^(a) is as defined above.

[0063] In one aspect, such compounds are described wherein R^(a) isselected from the group consisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl,C₃₋₆cycloalkylalkyl, arylalkyl, and heteroarylalkyl, wherein each ofsaid cycloalkyl, aryl, or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino,dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl,alkylsulfonyloxy, and halogen, and each of said amino groups isoptionally monosubstituted or disubstituted with alkyl.

[0064] In another aspect, such compounds are described wherein R² isC₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar is a 2,4-disubstituted or2,4,6-trisubstituted phenyl, and the substituents are independentlyselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen,haloalkyl, cyano, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen andC₁₋₉alkyl.

[0065] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted phenyl, and the substituents areeach independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) 0 are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

[0066] R¹ is aryl or heteroaryl, where said aryl or heteroaryl isoptionally substituted with one or more substituents independentlyselected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl,halogen, haloalkyl, cyano, nitro, and —NR^(a′)R^(b′), where R^(a′) andR^(b′) are each independently selected from the group consisting ofhydrogen, C₁₋₉alkyl, and C₁₋₉alkylcarbonyl.

[0067] In one alternative, such compounds are described wherein the arylor heteroaryl is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl,cyano, and —NR^(a′)R^(b′), where R^(a′) and R^(b′) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl.

[0068] In another embodiment, compounds of Formula III are described,wherein Ar is a di- or tri-substituted pyridinyl, and the substituentsare each independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, and R¹, R², R³, and R⁴are as defined above.

[0069] In one aspect, such compounds are described wherein R³ and R⁴ areeach independently selected from hydrogen and methyl.

[0070] In another aspect, such compounds are described wherein Ar is a2,4-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstitutedpyridin-3-yl, and the substituents are each independently selected fromthe group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl,dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and—NR^(a″)R^(b″), where R^(a″) 0 and R^(b″) are each independentlyselected from the group consisting of hydrogen, C₁₋₉alkyl, andC₁₋₉alkylcarbonyl.

[0071] In another aspect, such compounds are described wherein Ar is a2,4-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstitutedpyridin-3-yl, and the substituents are each independently selected fromthe group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl,alkylamino, and dialkylamino.

[0072] In another aspect, such compounds are described wherein R² ishydrogen, C₁₋₆alkyl, or C₁₋₆alkylcarbonyl.

[0073] In another embodiment, compounds of Formula IV are describedwherein Ar is a 2,4-disubstituted, 2,6-disubstituted, or2,4,6-trisubstituted pyridin-3-yl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, halogen, haloalkyl, alkylamino, and dialkylamino, R² ishydrogen, C₁₋₆alkyl, or C₁₋₆alkylcarbonyl, R³ and R⁴ are eachindependently selected from hydrogen and methyl; and R¹ is as definedabove.

[0074] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted pyridinyl, and the substituentsare each independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉ alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

[0075] R¹ is —CR^(c)R^(d)R^(e); R^(c) is hydroxy; and R^(d) and R^(e)are as defined above.

[0076] In one aspect, such compounds are described wherein R^(d) andR^(e) are each independently selected from the group consisting ofhydrogen, C₁₋₉alkyl, C₁₋₆alkoxyalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl,where each of said aryl or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen.

[0077] In one alternative, such compounds are described wherein R^(d)and R^(e) are each independently selected from the group consisting ofC₁₋₉alkyl, C₁₋₆alkoxyalkyl, aryl, and heteroaryl, where each of saidaryl or heteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen.

[0078] In another aspect, such compounds are described wherein R² isC₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar is a 2,4-disubstituted,2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and thesubstituents are each independently selected from the group consistingof C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl, and —NR^(a″)R^(b″), whereR^(a″) and R^(b″) are each independently selected from the groupconsisting of hydrogen and C₁₋₉alkyl.

[0079] In another alternative, such compounds are described whereinR^(d) and R^(e) are taken together to form a cycloalkyl or heterocyclylgroup.

[0080] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted pyridinyl, and the substituentsare each independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

[0081] R¹ is —CR^(c)R^(d)R^(e); R^(e) is selected from the groupconsisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl,where each of said aryl or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen; and R^(c)and R^(d) are taken together to form a divalent group selected fromC₁₋₆alkylidenyl, C₁₋₆heteroalkylidenyl, C₃₋₆cycloalkylidenyl,C₃₋₆cycloalkyl-alkylidenyl, C₃₋₆cycloalkylalkyl-alkylidenyl,C₃₋₆heterocyclylidenyl, C₃₋₆heterocyclyl-C₁₋₃alkylidenyl,C₃₋₆heterocyclylalkyl-C₁₋₃alkylidenyl, aryl-C₁₋₃alkylidenyl,aryl-C₁₋₃alkyl-alkylidenyl, heteroaryl-C₁₋₃alkylidenyl, andheteroarylalkyl-C₁₋₃alkylidenyl, wherein each of said cycloalkyl, aryl,or heteroaryl groups is optionally substituted with one or moresubstituents independently selected from C₁₋₆alkyl, haloalkyl,C₁₋₆alkoxy, amino, alkylamino, dialkylamino, and halogen.

[0082] In one alternative, such compounds are described wherein R^(c)and R^(d) are taken together to form a divalent group selected fromC₁₋₆alkylidenyl, C₃₋₆cycloalkyl-alkylidenyl, aryl-C₁₋₃alkylidenyl, andheteroaryl-C₁₋₃alkylidenyl, wherein each of said aryl or heteroarylgroups is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino,alkylamino, dialkylamino, and halogen.

[0083] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted pyridinyl, and the substituentsare each independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(″) and R^(b″) are each independentlyselected from the group consisting of hydrogen, C₁₋₉alkyl, andC₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above; and

[0084] R¹ is —CR^(c)R^(d)R^(e); R^(e) is selected from the groupconsisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl, and heteroaryl, where theheteroaryl is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆alkyl,haloalkyl, C₁₋₆alkoxy, and halogen; and R^(c) and R^(d) are takentogether to form a divalent group selected from C₁₋₆alkylidenyl,C₃₋₆cycloalkyl-alkylidenyl, C₃₋₆heterocyclyl-C₁₋₃alkylidenyl,aryl-C₁₋₃alkylidenyl, and heteroaryl-C₁₋₃alkylidenyl, wherein each ofsaid aryl, or heteroaryl groups is optionally substituted with one ormore substituents independently selected from C₁₋₆alkyl, C₁₋₆alkoxy,amino, alkylamino, and dialkylamino.

[0085] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted pyridinyl, and the substituentsare each independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

[0086] R¹ is —CR^(c)R^(d)R^(e); R^(c) is hydrogen; and R^(d) and R^(e)are as defined above.

[0087] In one aspect, such compounds are described wherein R^(d) andR^(e) are each independently selected from the group consisting ofC₁₋₉alkyl, C₁₋₆alkoxyalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl, where each of said aryl orheteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen.

[0088] In one alternative, such compounds are described wherein R^(d)and R^(e) are each independently selected from the group consisting ofC₁₋₉alkyl, C₁₋₆alkoxyalkyl, aryl, and heteroaryl, where each of saidaryl or heteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen; R² is C₁₋₆alkyl; R³ andR⁴ are hydrogen; and Ar is a 2,4-disubstituted, 2,6-disubstituted, or2,4,6-trisubstituted pyridin-3-yl, and the substituents areindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, halogen, haloalkyl, and —NR^(a″)R^(b″), where R^(a″) andR^(b″) are each independently selected from the group consisting ofhydrogen and C₁₋₉alkyl.

[0089] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted pyridinyl, and the substituentsare each independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

[0090] R¹ is —NR^(a)R^(b); —C(O)NR^(a)R^(b); or —CR^(c)R^(d)R^(e), whereR^(c) is —NR^(a′″)R^(b′″); R^(d) and R^(e) are each independentlyselected from the group consisting of hydrogen and C₁₋₉alkyl; and R^(a),R^(b), R^(a′″), and R^(b′″) are as defined above.

[0091] In one alternative, such compounds are described wherein R^(a),R^(b), R^(a′″), and R^(b′″) are each independently selected from thegroup consisting of hydrogen, C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,C₃₋₆cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl,wherein each of said aryl or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino,dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl,alkylsulfonyloxy, and halogen, and each of said amino groups isoptionally monosubstituted or disubstituted with alkyl.

[0092] In another alternative, such compounds are described whereinR^(a) and R^(b), or R^(a′″) and R^(b′″), are taken together with thenitrogen to which they are attached form an heterocyclyl ring selectedfrom the group consisting of pyrrolidine, piperidine, homopiperidine,tetrahydropyridine, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine,hexahydropyrimidine, pyrazolidine, piperazine, morpholine, andimidazoline, where each of said rings is optionally substituted with oneor more substituents independently selected from the group consisting ofhydroxy, oxo, alkyl, aminoalkyl, acyl, acylamino, aminocarbonyl,aminocarbonylalkyl, and aminocarbonylamino, and each of said aminogroups is optionally monosubstituted or disubstituted with alkyl, or iscontained in a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinylgroup.

[0093] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted pyridinyl, and the substituentsare each independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁-alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

[0094] R¹ is —NR^(a)R^(b); R^(a) is selected from the group consistingof hydrogen, C₁₋₉alkyl, and C₁₋₆alkoxyalkyl; and R^(b) is selected fromthe group consisting of C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,heterocyclylalkyl, arylalkyl, and heteroarylalkyl, wherein each of saidaryl or heteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, andhalogen, and each of said amino groups is optionally monosubstituted ordisubstituted with alkyl.

[0095] In one alternative, such compounds are described, wherein R² isC₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar is a 2,4-disubstituted,2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and thesubstituents are independently selected from the group consisting ofC₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl, and —NR^(a″)R^(b″), whereR^(a″) and R^(b″) are each independently selected from the groupconsisting of hydrogen and C₁₋₉alkyl.

[0096] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted pyridinyl, and the substituentsare each independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

[0097] R¹ is —CR^(c)R^(d)R^(e); R^(c) is —NR^(a′″)R^(b′″); R^(d) andR^(e) are each independently selected from the group consisting ofhydrogen and C₁₋₉alkyl; R^(a′″) is selected from the group consisting ofhydrogen, C₁₋₉alkyl, and C₁₋₆alkoxyalkyl; and R^(b′″) is selected fromthe group consisting of C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,heterocyclylalkyl, arylalkyl, and heteroarylalkyl, wherein each of saidaryl or heteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, andhalogen, and each of said amino groups is optionally monosubstituted ordisubstituted with alkyl.

[0098] In one alternative, such compounds are described wherein R² isC₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar is a 2,4-disubstituted,2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and thesubstituents are independently selected from the group consisting ofC₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl, and —NR^(a″)R^(b″), whereR^(a″) and R^(b″) are each independently selected from the groupconsisting of hydrogen and C₁₋₉alkyl.

[0099] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted pyridinyl, and the substituentsare each independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) 0 are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

[0100] R¹ is —OR^(a), and R^(a) is as defined above.

[0101] In one alternative, such compounds are described wherein R^(a) isselected from the group consisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl,C₃₋₆cycloalkylalkyl, arylalkyl, and heteroarylalkyl, wherein each ofsaid cycloalkyl, aryl, or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino,dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl,alkylsulfonyloxy, and halogen, and each of said amino groups isoptionally monosubstituted or disubstituted with alkyl.

[0102] In another alternative, such compounds are described wherein R²is C₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar is a 2,4-disubstituted,2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and thesubstituents are independently selected from the group consisting ofC₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl, and —NR^(a″)R^(b″), whereR^(a″) and R^(b″) are each independently selected from the groupconsisting of hydrogen and C₁₋₉alkyl.

[0103] In another embodiment, compounds of Formula III are described,wherein R³ and R⁴ are each independently selected from hydrogen andmethyl, Ar is a di- or tri-substituted pyridinyl, and the substituentsare each independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

[0104] R¹ is aryl or heteroaryl, where said aryl or heteroaryl isoptionally substituted with one or more substituents independentlyselected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl,halogen, haloalkyl, cyano, nitro, and —NR^(a′)R^(b′), where R^(a′) andR^(b′) are each independently selected from the group consisting ofhydrogen, C₁₋₉alkyl, and C₁₋₉alkylcarbonyl.

[0105] In one alternative, such compounds are described wherein the arylor heteroaryl is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl,cyano, and —NR^(a′)R^(b′), where R^(a′) and R^(b′) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl.

[0106] The invention further relates to pharmaceutical compositionscontaining a therapeutically effective amount of at least one compoundof Formula I or Formula II, or individual isomers, racemic ornon-racemic mixtures of isomers, or pharmaceutically acceptable salts orsolvates thereof, in admixture with at least one suitable carrier.

[0107] The invention further relates to a method of treating a subjectthat has a disease state that is alleviated by treatment with a CRFreceptor antagonist, wherein said method comprises administering to saidsubject a therapeutically effective amount of the compound of Formula Ior Formula II.

[0108] In one embodiment, a method of treating a subject that has adisease state comprising disorders of the CNS is described herein. Inanother embodiment, a method of treating a subject with a disease statecomprising phobias, stress related illnesses, mood disorders, eatingdisorders, generalized anxiety disorders, stress inducedgastrointestinal dysfunctions, neurodegenerative diseases, orneuropsychiatric disorders is described herein.

[0109] The invention further relates to a process for preparing acompound of Formula I, where a is a single bond, comprising:

[0110] (a) treating a compound of formula:

[0111] where R³, R⁴, and Ar are as defined in claim 1, with a compoundof formula:

[0112] where R is alkyl, to form a first intermediate of formula:

[0113] (b) treating the first intermediate with a compound of formula:

R²—NHNH₂,

[0114] where R² is as defined in claim 1, to form a second intermediateof formula:

[0115] In one embodiment, the process further comprises (c) treating thesecond intermediate with a compound of formula:

R^(a)—OH,

[0116] where R^(a) is as defined in claim 1, to form a compound ofFormula I, wherein R¹ is —OR^(a).

[0117] In one alternative, the process further comprises (c) treatingthe second intermediate with a brominating reagent to form a thirdintermediate of formula:

[0118] In another embodiment, the process further comprises (d)converting the third intermediate into an anion of formula:

[0119] (e) treating the anion with a compound of formula:

[0120] where R^(d) and R^(e) are as defined in claim 1, to form acompound of Formula I, wherein R¹ is —CR^(c)R^(d)R^(e), and R^(c) ishydroxy.

[0121] In one alternative, the process further comprises (e) treatingthe anion with a compound of formula:

C(O)₂,

[0122] to form a compound of Formula I, wherein R¹ is —CO₂R^(a).

[0123] In another embodiment, the process further comprises (d) treatingthe third intermediate with a compound of formula:

[0124] where Ar′ is aryl or heteroaryl, where each aryl or heteroaryl isoptionally substituted with one or more substituents independentlyselected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl,halogen, haloalkyl, cyano, nitro, and —NR^(a′)R^(b′), where R^(a′) andR^(b′) are each independently selected from the group consisting ofhydrogen, C₁₋₉alkyl, and C₁₋₉alkylcarbonyl, to form a compound ofFormula I, wherein R¹ is aryl or heteroaryl, where each aryl orheteroaryl is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, halogen, haloalkyl, cyano, nitro, and —NR^(a′)R^(b′),where R^(a′) and R^(b′) are each independently selected from the groupconsisting of hydrogen, C₁₋₉alkyl, and C₁₋₉alkylcarbonyl.

DETAILED DESCRIPTION OF THE INVENTION Definitions

[0125] Unless otherwise stated, the following terms used in thisApplication, including the specification and claims, have thedefinitions given below. It must be noted that, as used in thespecification and the appended claims, the singular forms “a”, “an,” and“the” include plural referents unless the context clearly dictatesotherwise.

[0126] “Alkyl” or “lower alkyl” means a monovalent linear or branchedsaturated hydrocarbon radical, consisting solely of carbon and hydrogenatoms, having from one to six carbon atoms inclusive, unless otherwiseindicated. Examples of alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl,pentyl, n-hexyl, and the like.

[0127] “Alkylene” means a divalent linear or branched saturatedhydrocarbon radical consisting solely of carbon and hydrogen atoms,having from one to six carbon atoms inclusive, unless otherwiseindicated. Examples of alkylene radicals include, but are not limitedto, methylene, ethylene, propylene, 2-methylethylene, 3-methylpropylene,2-ethylethylene, pentylene, hexylene, and the like.

[0128] “Alkoxy” means a radical —OR, wherein R is a lower alkyl radicalas defined herein. Examples of alkoxy radicals include, but are notlimited to, methoxy, ethoxy, isopropoxy, and the like.

[0129] “Alkoxyalkyl” denotes one or more alkoxy group(s) as definedabove which is (are) bonded to an alkyl group as defined above. Examplesare methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl,ethoxyethyl, ethoxypropyl, propyloxypropyl, methoxybutyl, ethoxybutyl,propyloxybutyl, butyloxybutyl, t-butyloxybutyl, methoxypentyl,ethoxypentyl, propyloxypentyl,1,4-dimethoxypropyl, including theirisomers. C₁₋₆ alkoxyalkyl denotes a group wherein the alkyl portion iscomprised of 1-6 carbon atoms exclusive of carbon atoms in the alkoxyportion of the group.

[0130] “Cycloalkyl” means a monovalent saturated carbocyclic radicalconsisting of one or more rings, which can optionally be substitutedwith hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halo,haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino,dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl, andsulfonylamino, unless otherwise indicated. Examples of cycloalkylradicals include, but are not limited to, cyclopropyl, cyclobutyl,3-ethylcyclobutyl, cyclopentyl, cycloheptyl, and the like.

[0131] “Cycloalkylalkyl” means a radical —R′R″, wherein R′ is analkylene radical, and R″ is a cycloalkyl radical as defined herein.Examples of cycloalkylalkyl radicals include, but are not limited to,cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl, and the like.

[0132] “Cycloalkenyl” means a monovalent unsaturated carbocyclic radicalconsisting of one or more rings, which can optionally be substitutedwith hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halo,haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino,dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl, andsulfonylamino, unless otherwise indicated. Examples of cycloalkenylradicals include, but are not limited to, cyclobuten-1-yl,3-ethylcyclobuten-1-yl, cyclopenten-1-yl, 3-fluorocyclohepten-1-yl, andthe like.

[0133] “Halogen” or “halo” means the radical fluoro, bromo, chloro, oriodo, and combinations thereof.

[0134] “Haloalkyl” means a lower alkyl radical as defined hereinsubstituted in any position with one or more halogen atoms as definedherein. Examples of haloalkyl radicals include, but are not limited to,1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like.

[0135] “Aryl” means a monocyclic or bicyclic radical of 6 to 12 ringcarbon atoms having at least one aromatic ring, with the understandingthat the attachment point of the aryl radical will be on an aromaticring. The aryl radical is optionally substituted independently with oneor more substituents, preferably one to three substituents, selectedfrom alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, acyl, acylamino,amino, alkylamino, dialkylamino, alkylthio, alkylsulfinyl,alkylsulfonyl, alkylsulfonyloxy, —SO2NR′R″ (where R′ and R″ areindependently hydrogen or alkyl), alkoxy, haloalkoxy, alkoxycarbonyl,carbamoyl, hydroxy, halo, nitro, cyano, thio, methylenedioxy orethylenedioxy. More specifically the term aryl includes, but is notlimited to, phenyl, naphthyl, tetrahydronaphthyl,3,4-methylenedioxyphenyl, 1,2,3,4-tetrahydroquinolin-7-yl,1,2,3,4-tetrahydroisoquinoline-7-yl, and the like.

[0136] “Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12ring atoms having at least one aromatic ring containing one, two, orthree ring heteroatoms selected from nitrogen, oxygen, and sulfur, theremaining ring atoms being carbon, with the understanding that theattachment point of the heteroaryl radical will be on an aromatic ring.The heteroaryl ring is optionally substituted independently with one ormore substituents, preferably one or two substituents, selected fromalkyl, haloalkyl, hydroxyalkyl, heteroalkyl, acyl, acylamino, amino,alkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl,alkylsulfonyloxy, —SO₂NR′R″ (where R′ and R″ are independently hydrogenor alkyl), alkoxy, haloalkoxy, alkoxycarbonyl, carbamoyl, hydroxy, halo,nitro, cyano, thio, methylenedioxy or ethylenedioxy. More specificallythe term heteroaryl refers to monocyclic aromatic moieties having 5 to 6ring atoms, including 1 to 2 heteroatoms, and includes, but is notlimited to, pyridinyl, furanyl, thienyl, thiazolyl, isothiazolyl,triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, and pyrimidinyl,and derivatives thereof. In addition, the term heteroaryl refers tobicyclic aromatic moieties having 9 to 10 ring atoms, including 1 to 3heteroatoms, and includes, but is not limited to, benzofuranyl,tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl,benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl,quinolinyl, 5,6,7,8-tetrahydroquinolinyl, isoquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, benzimidazolyl, benzisoxazolyl, andbenzothienyl, and derivatives thereof.

[0137] “Heteroalkyl” means an alkyl radical as defined herein whereinone, two, or three hydrogen atoms have been replaced with a substituentindependently selected from the group consisting of —OR^(a),—NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is an integer from 0 to 2),with the understanding that the point of attachment of the heteroalkylradical is through a carbon atom, wherein R^(a) is hydrogen, acyl,alkyl, cycloalkyl, or cycloalkylalkyl; and R^(b) and R^(c) areindependently selected from the group consisting of hydrogen, acyl,alkyl, cycloalkyl, or cycloalkylalkyl; and when n is 0, R^(d) ishydrogen, alkyl, cycloalkyl, and cycloalkylalkyl. When n is 1 or 2,R^(d) is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino,monoalkylamino, or dialkylamino. Representative examples include, butare not limited to, 2-hydroxyethyl, 3-hydroxypropyl,2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,2-hydroxy-1-methylpropyl, 2-methoxyethyl, 2-ethoxyethyl,3-methoxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl,aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl,methylaminosulfonylmethyl, methylaminosulfonylethyl,methylaminosulfonylpropyl, and the like.

[0138] “Heterocyclyl” means a saturated or unsaturated non-aromaticmonocyclic or bicylic radical of 3 to 10 ring atoms in which one or tworing atoms are heteroatom containing groups selected from NR′, O, orS(O)_(n) (where R′ is alkyl, heteroalkyl, or hydrogen, and n is aninteger from 0 to 2), the remaining ring atoms being carbon. Theheterocyclyl radical is optionally substituted with one or moresubstituents selected from the group consisting of hydroxy, oxo, alkyl,haloalkyl, hydroxyalkyl, heteroalkyl, and acyl. The term heterocyclylincludes, but is not limited to, tetrahydropyranyl, piperidino,tetrahydropyrimidin-5-yl, tetrahydropyrimidin-1-yl,N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl,3-pyrrolidino, morpholino, thiomorpholino, thiomorpholino-1-oxide,thiomorpholino-1,1-dioxide, pyrrolinyl, imidazolinyl,tetrahydroquinolin-1-yl and tetrahydroisoquinolin-2-yl, and the like.

[0139] “Arylalkyl” means a radical —R′R″ where R′ is an alkylene radicaland R″ is an aryl radical as defined herein. Examples of arylalkylradicals include, but are not limited to, 4-fluorophenylmethyl,3,4-dichlorophenylethyl, and the like.

[0140] “Heteroarylalkyl” means a radical —R′R″ where R′ is an alkyleneradical and R″ is an heteroaryl radical as defined herein. Examples ofheteroarylalkyl radicals include, but are not limited to, such as3-pyridinylmethyl, 4-chloropyrimidin-2-ylmethyl, 2-thiophen-2-ylethyl,and the like.

[0141] “Heterocyclylalkyl” means a radical —R′R″ where R′ is an alkyleneradical and R″ is an heterocyclyl radical as defined herein. Examples ofheterocyclylalkyl radicals include, but are not limited to,tetrahydropyran-2-ylmethyl, 2-piperidinylmethyl, 3-piperidinylmethyl,morpholin-1-ylpropyl, and the like.

[0142] “Alkylamino” means a radical —NR′R″, wherein R′ is hydrogen oralkyl, and R″ is an alkyl radical as defined herein. Examples ofalkylamino radicals include, but are not limited to, methylamino,ethylamino, cyclopropylmethylamino, dicyclopropylmethylamino,dimethylamino, methylethylamino, diethylamino, di(1-methylethyl)amino,and the like.

[0143] “Acyl” means a formyl radical of the formula —C(O)H, or acarbonyl radical of the formula —C(O)R′, where R′ is selected from thegroup consisting of C₁₋₁₈alkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heteroalkyl, heterocyclyl,heterocyclylalklyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, or amino, as defined herein, where said amino is optionallymonosubstituted or disubstituted with alkyl, or said amino is containedin a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl group.

[0144] “Alkylidenyl” means a bivalent radical=CRR′, wherein R and R′ areindependently an alkyl radical or hydrogen, as defined herein. Examplesof alkylidenyl radicals include, but are not limited to, ethylidenyl,propylidenyl, butylidenyl, and the like.

[0145] “Cycloalkylidenyl” means a bivalent radical=CRR′, wherein R andR′ are taken together with the carbon to which they are attached to forma bivalent cycloalkyl radical, as defined herein. Examples ofcycloalkylidenyl radicals include, but are not limited to,cyclopentylidenyl, 3-fluorocyclohexylidenyl, and the like.

[0146] “Cycloalkyl-alkylidenyl” means a bivalent radical=CRR′, wherein Ris an alkyl radical or hydrogen, and R′ is a cycloalkyl radical, asdefined herein. Examples of cycloalkyl-alkylidenyl radicals include, butare not limited to, cyclopropylmethylidenyl, cyclohexylmethylidenyl,1-cyclopentylethylidenyl, and the like.

[0147] “Cycloalkylalkyl-alkylidenyl” means a bivalent radical=CRR′,wherein R is an alkyl radical or hydrogen, and R′ is a cycloalkylalkylradical, as defined herein. Examples of cycloalkylalkyl-alkylidenylradicals include, but are not limited to, 2-cyclopentylethylidenyl,1-cyclohexylpropyliden-2-yl, and the like.

[0148] “Heteroalkylidenyl” means a bivalent radical=CRR′, wherein R isan heteroalkyl radical, an haloalkyl radical, an alkyl radical, orhydrogen, and R′ is an heteroalkyl radical or an haloalkyl radical, asdefined herein. Examples of heteroalkylidenyl radicals include, but arenot limited to, 3,3,3-trifluoropropylidenyl, 2-hydroxybutylidenyl,3-aminopropylidenyl, and the like.

[0149] “Heterocyclylidenyl” means a bivalent radical=CRR′, wherein R andR′ are taken together with the carbon to which they are attached to forma bivalent heterocyclyl radical, as defined herein. Examples ofheterocyclylidenyl radicals include, but are not limited to,pyrrolidinyliden-2-yl, tetrahydropyranyliden-4-yl, piperidinyliden-4-yl,and the like.

[0150] “Heterocyclyl-alkylidenyl” means a bivalent radical=CRR′, whereinR is an alkyl radical or hydrogen, and R′ is an heterocyclyl radical, asdefined herein. Examples of heterocyclyl-alkylidenyl radicals include,but are not limited to, 4-piperidinylmethylidenyl,4-methyl-1-piperazinylmethylidene, and the like.

[0151] “Heterocyclylalkyl-alkylidenyl” means a bivalent radical=CRR′,wherein R is an alkyl radical or hydrogen, and R′ is anheterocyclylalkyl radical, as defined herein. Examples ofheterocyclylalkyl-alkylidenyl radicals include, but are not limited to,2-(tetrahydropyran-4-yl)ethylidenyl, 1-(piperidin-3-yl)propyliden-2-yl,and the like.

[0152] “Arylalkylidenyl” means a bivalent radical=CRR′, wherein R is anaryl radical, an alkyl radical, or hydrogen, and R′ is an aryl radical,as defined herein. Examples of arylalkylidenyl radicals include, but arenot limited to, 4-chlorophenylmethylidenyl,6,7-dimethoxynaphth-2-ylmethylidenyl, and the like.

[0153] “Arylalkyl-alkylidenyl” means a bivalent radical=CRR′, wherein Ris an alkyl radical or hydrogen, and R′ is an arylalkyl radical, asdefined herein. Examples of arylalkyl-alkylidenyl radicals include, butare not limited to, 2-(4-trifluoromethylphenyl)ethylidenyl,1-(3,4-dichlorophenyl)propyliden-2-yl, and the like.

[0154] “Heteroarylalkylidenyl” means a bivalent radical=CRR′, wherein Ris an alkyl radical or hydrogen, and R′ is an heteroaryl radical, asdefined herein. Examples of heteroarylalkylidenyl radicals include, butare not limited to, 3-pyridinylmethylidenyl,4-chloro-2-pyrimidinylmethylidenyl, and the like.

[0155] “Heteroarylalkyl-alkylidenyl” means a bivalent radical=CRR′,wherein R is an alkyl radical or hydrogen, and R′ is an heteroarylalkylradical, as defined herein. Examples of heteroarylalkyl-alkylidenylradicals include, but are not limited to,2-(4-trifluoromethylpyrimidinyl)ethylidenyl,1-(thiophen-2-yl)propyliden-2-yl, and the like.

[0156] “Phenylsulfonyl” means a monovalent radical C₆H₅SO₂—. A phenylgroup can be unsubstituted or substituted with one or more suitablesubstituents.

[0157] “Alkoxycarbonyl” means a monovalent radical —C(O)—OR, wherein Ris a lower alkyl radical as defined herein. Examples of alkoxycarbonylradicals include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, butoxycarbonyl, and the like.

[0158] “Alkoxyalkylcarbonyl” means a monovalent radical —C(O)—R—OR′,wherein R is an alkylene radical as defined herein and R′ is a loweralkyl radical as defined herein. Examples of alkoxyalkylcarbonylradicals include, but are not limited to, methoxymethylcarbonyl,ethoxymethylcarbonyl, and the like.

[0159] It is contemplated that the definitions described herein may beappended to form chemically-relevant combinations, such as“heteroalkylaryl,” “haloalkylheteroaryl,” “arylalkylheterocyclyl,”“alkylcarbonyl,” “alkoxyalkyl,” and the like.

[0160] “Optional” or “optionally” means that a subsequently describedevent or circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optional bond” means that the bondmay or may not be present, and that the description includes single,double, or triple bonds.

[0161] “Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under alkylating conditions. Examples of leavinggroups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

[0162] “Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive oxygen atoms present in thereactants. Acceptable protective groups for alcoholic or phenolichydroxyl groups, which may be removed successively and selectivelyinclude hydroxyl groups protected as acetates, haloalkyl carbonates,benzyl ethers, alkylsilyl ethers, heterocyclyl ethers, methyl or alkylethers, and the like. Protective or blocking groups for carboxyl groupsare similar to those described for hydroxyl groups, and are preferablytert-butyl, benzyl or methyl esters.

[0163] “Amino-protecting group” means the protecting group that refersto those organic groups intended to protect the nitrogen atom againstundesirable reactions during synthetic procedures and includes, but isnot limited to, benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ),p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,tert-butoxycarbonyl (BOC), trifluoroacetyl, and the like. It ispreferred to use either BOC or CBZ as the amino-protecting group becauseof the relative ease of removal, for example by exposure to mild acidsin the case of BOC, e.g., trifluoroacetic acid or hydrochloric acid inethyl acetate as a solvent; or by catalytic hydrogenation in the case ofCBZ.

[0164] “Hydroxy-protecting group” means the protecting group thatpreserves a hydroxy group that otherwise would be modified by certainchemical reactions. Suitable hydroxy-protecting groups includeether-forming groups that can be removed easily after completion of allother reaction steps, such as the benzyl or the trityl group optionallysubstituted in their phenyl ring. Other suitable hydroxy-protectinggroups include alkyl ether groups, the tetrahydropyranyl, silyl,trialkylsilyl ether groups, and the allyl group.

[0165] “Deprotection” or “deprotecting” means the process by which aprotective group is removed after the selective reaction is completed.Certain protective groups may be preferred over others due to theirconvenience or relative ease of removal. Deprotecting reagents forprotected hydroxyl or carboxyl groups include potassium or sodiumcarbonates, lithium hydroxide in alcoholic solutions, zinc in methanol,acetic acid, trifluoroacetic acid, palladium catalysts, or borontribromide, and the like.

[0166] “Inert organic solvent” or “inert solvent” means the solventinert under the conditions of the reaction being described inconjunction therewith, including for example, benzene, toluene,acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform,methylene chloride or dichlbromethane, dichloroethane, diethyl ether,ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol,propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like.Unless specified to the contrary, the solvents used in the reactions ofthe present invention are inert solvents.

[0167] “Isomerism” means compounds that have identical molecularformulae but that differ in the nature or the sequence of bonding oftheir atoms or in the arrangement of their atoms in space. Isomers thatdiffer in the arrangement of their atoms in space are termed“stereoisomers”. Stereoisomers that are not mirror images of one anotherare termed “diastereoisomers”, and stereoisomers that arenon-superimposable mirror images are termed “enantiomers”, or sometimesoptical isomers. A carbon atom bonded to four nonidentical substituentsis termed a “chiral center”.

[0168] “Chiral isomer” means a compound with one chiral center. It hastwo enantiomeric forms of opposite chirality and may exist either as anindividual enantiomer or as a mixture of enantiomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”. A compound that has more thanone chiral center has 2^(n−1) enantiomeric pairs, where n is the numberof chiral centers. Compounds with more than one chiral center may existas either an individual diastereomer or as a mixture of diastereomers,termed a “diastereomeric mixture.” When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al. Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn etal. Angew. Chem. 1966, 78, 413; Cahn and Ingold J. Chem. Soc. (London)1951, 612; Cahn et al. Experientia 1956, 12, 81; Cahn, J. Chem. Educ.1964,41, 116).

[0169] “Geometric Isomers” means the diastereomers that owe theirexistence to hindered rotation about double bonds. These configurationsare differentiated in their names by the prefixes cis and trans, or Zand E, which indicate that the groups are on the same or opposite sideof the double bond in the molecule according to the Cahn-Ingold-Prelogrules.

[0170] “Atropic isomers” means the isomers owing their existence torestricted rotation caused by hindrance of rotation of large groupsabout a central bond.

[0171] “Substantially pure” means at least about 90 mole percent, morepreferably at least about 95 mole percent, and most preferably at leastabout 98 mole percent of the desired enantiomer or stereoisomer ispresent compared to other possible configurations.

[0172] “Pharmaceutically acceptable” means that which is useful inpreparing a pharmaceutical composition that is generally safe,non-toxic, and neither biologically nor otherwise undesirable andincludes that which is acceptable for veterinary as well as humanpharmaceutical use.

[0173] “Pharmaceutically acceptable salts” of a compound means saltsthat are pharmaceutically acceptable, as defined herein, and thatpossess the desired pharmacological activity of the parent compound.Such salts include:

[0174] (1) acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid,citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid,gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid,2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,malonic acid, mandelic acid, methanesulfonic acid, muconic acid,2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinicacid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, andthe like; or

[0175] (2) salts formed when an acidic proton present in the parentcompound either is replaced by a metal ion, e.g., an alkali metal ion,an alkaline earth ion, or an aluminum ion; or coordinates with anorganic or inorganic base. Acceptable organic bases includediethanolamine, ethanolamine, N-methylglucamine, triethanolamine,tromethamine, and the like. Acceptable inorganic bases include aluminumhydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate andsodium hydroxide.

[0176] The preferred pharmaceutically acceptable salts are the saltsformed from acetic acid, hydrochloric acid, sulphuric acid,methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid,citric acid, sodium, potassium, calcium, zinc, and magnesium. It shouldbe understood that all references to pharmaceutically acceptable saltsinclude solvent addition forms (solvates) or crystal forms (polymorphs)as defined herein, of the same acid addition salt.

[0177] “Crystal forms” (or polymorphs) means crystal structures in whicha compound can crystallize in different crystal packing arrangements,all of which have the same elemental composition. Different crystalforms usually have different X-ray diffraction patterns, infraredspectra, melting points, density, hardness, crystal shape, optical andelectrical properties, stability and solubility. Recrystallizationsolvent, rate of crystallization, storage temperature, and other factorsmay cause one crystal form to dominate.

[0178] “Solvates” means solvent additions forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

[0179] “Prodrug” or “pro-drug” means a pharmacologically inactive formof a compound which must be metabolized in vivo, e.g., by biologicalfluids or enzymes, by a subject after administration into apharmacologically active form of the compound in order to produce thedesired pharmacological effect. Prodrugs of a compound of Formula I orFormula II are prepared by modifying one or more functional group(s)present in the compound of Formula I or Formula II in such a way thatthe modification(s) may be cleaved in vivo to release the parentcompound. Prodrugs include compounds of Formula I or Formula II whereina hydroxy, amino, sulfhydryl, carboxy or carbonyl group in a compound ofFormula I or Formula II is bonded to any group that may be cleaved invivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy orcarbonyl group respectively. Examples of prodrugs include, but are notlimited to, esters (e.g. acetate, dialkylaminoacetates, formates,phosphates, sulfates and benzoate derivatives) and carbamates of hydroxyfunctional groups (e.g. N,N-dimethylcarbonyl), esters of carboxylfunctional groups (e.g. ethyl esters, morpholinoethanol esters), N-acylderivatives (e.g. N-acetyl), N-Mannich bases, Schiff bases andenaminones of amino functional groups, oximes, acetals, ketals, and enolesters of ketones and aldehyde functional groups in compounds of FormulaI or Formula II, and the like.

[0180] The prodrug can be metabolized before absorption, duringabsorption, after absorption, or at a specific site. Although metabolismoccurs for many compounds primarily in the liver, almost all othertissues and organs, especially the lung, are able to carry out varyingdegrees of metabolism. Prodrug forms of compounds may be utilized, forexample, to improve bioavailability, improve subject acceptability suchas by masking or reducing unpleasant characteristics such as bittertaste or gastrointestinal irritability, alter solubility such as forintravenous use, provide for prolonged or sustained release or delivery,improve ease of formulation, or provide site-specific delivery of thecompound. Reference to a compound herein includes prodrug forms of acompound. Prodrugs are described in The Organic Chemistry of Drug Designand Drug Action, by Richard B. Silverman, Academic Press, San Diego,1992. Chapter 8: “Prodrugs and Drug delivery Systems” pp.352-401; Designof Prodrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985;Design of Biopharmaceutical Properties through Prodrugs and Analogs. Ed.by E. B. Roche, American Pharmaceutical Association, Washington, 1977;and Drug Delivery Systems, ed. by R. L. Juliano, Oxford Univ. Press,Oxford, 1980.

[0181] “Subject” means mammals and non-mammals. Mammals means any memberof the Mammalia class including, but not limited to, humans; non-humanprimates such as chimpanzees and other apes and monkey species; farmanimals such as cattle, horses, sheep, goats, and swine; domesticanimals such as rabbits, dogs, and cats; laboratory animals includingrodents, such as rats, mice, and guinea pigs; and the like. Examples ofnon-mammals include, but are not limited to, birds, and the like. Theterm “subject” does not denote a particular age or sex.

[0182] “Therapeutically effective amount” means an amount of a compoundthat, when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgement of the attending medical or veterinarypractitioner, and other factors.

[0183] “Disease state” means any disease, condition, symptom, orindication.

[0184] “Treating” or “treatment” of a disease state includes:

[0185] (1) preventing the disease state, i.e. causing the clinicalsymptoms of the disease state not to develop in a subject that may beexposed to or predisposed to the disease state, but does not yetexperience or display symptoms of the disease state;

[0186] (2) inhibiting the disease state, i.e., arresting the developmentof the disease state or its clinical symptoms, or

[0187] (3) relieving the disease state, i.e., causing temporary orpermanent regression of the disease state or its clinical symptoms.

[0188] “Mood disorders” or “affective disorders” means psychopathologicconditions in which a pervasive disturbance of mood constitutes the coremanifestation. These terms subsume anxiety and related neuroses,especially the depressive form. Examples of “mood disorders” or“affective disorders” include, but are not limited to, depression, majordepressive disorder, single episode depression, recurrent depression,child abuse induced depression, postpartum depression, dysthemia,unipolar disorder, bipolar disorder with manifestations of insomnia andeating disorder, dysthymic disorder, double depression, morbid andclinical depression, mania and cyclothymia.

Nomenclature

[0189] In general, the nomenclature used in this Application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature.

[0190] For example, a compound of Formula I wherein R¹ is4-hydroxyheptan-4-yl, R² is methyl, R³, and R⁴ are hydrogen, Ar is2-chloro-4,6-dimethyl-phenyl, and n is 1 is named4-[7-(2-chloro-4,6-dimethyl-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-heptan-4-ol.

General Utility

[0191] The compounds of this invention are CRF antagonists, and as suchare expected to be effective in the treatment of a wide range ofstress-related illnesses, mood disorders such as depression, majordepressive disorder, single episode depression, recurrent depression,child abuse induced depression, postpartum depression, dysthemia,bipolar disorder and cyclothymia; chronic fatigue syndrome; eatingdisorders such as obesity, anorexia and bulimia nervosa; generalizedanxiety disorder; panic disorder; phobias; obsessive-compulsivedisorder; post-traumatic stress disorder; pain perception such asfibromyalgia; headache; stress-induced gastrointestinal dysfunction suchas irritable bowel syndrome (IBS), colonic hypersensitivity or spasticcolon; hemorrhagic stress; ulcers; stress-induced psychotic episodes;inflammatory disorders such as rheumatoid arthritis and osteoarthritis;asthma; psoriasis; allergies; premature birth; hypertension; congestiveheart failure; sleep disorders; neurodegenerative diseases such asAlzheimer's disease, senile dementia, Parkinsons's disease andHuntington's disease; head or spinal cord trauma; ischemic neuronaldamage; excitotoxic neuronal damage; epilepsy; stroke; psychosocialdwarfism; chemical dependencies and addictions; drug and alcoholwithdrawal symptoms; stress-induced immune dysfunctions; immunesuppression and stress-induced infections; cardiovascular or heartrelated diseases; fertility problems; and/or human immunodeficiencyvirus infections.

[0192] These and other therapeutic uses are described, for example, inGoodman & Gilman's, The Pharmacological Basis of Therapeutics, ninthedition, McGraw-Hill, New York, 1996, Chapter 26:601-616; and Coleman,R. A., Pharmacological Reviews, 1994,46:205-229.

Testing

[0193] The pharmacology of the compounds of this invention wasdetermined by art recognized procedures. The CRF receptor bindingaffinity of test compounds can be determined by the intracellular CRFstimulated cAMP activity assay and the CRF Receptor Binding Assay asdescribed in more detail in Example 3 and 4 respectively.

Compound Preparation

[0194] The compounds of Formulae I and II described herein may beprepared by standard synthetic methods. In particular, certain compoundsof Formulae I and II may be prepared from intermediate bromopyrazole 7,the preparation of which is illustrated in Scheme 1 for Formula I, whereR², R³, R⁴, and n are as described above, and Ar, as described above, isfor example phenyl optionally-substituted with one or more groups X.

[0195] According to Scheme 1, optionally substituted aniline 1 sacylated with a carboxylic acid derivative, optionally substituted withgroups R³ and R⁴, having an ω-leaving group, such as halogen, to provideamide 2, which is subsequently cyclized under basic conditions onto thecarbon possessing the leaving group to generate 3. Anilide lactam 3 isconverted into the corresponding thione 4, deprotonated, C-acylated, andconcurrently S-methylated to form methyl carboxylate 5. Treatment of 5with R²-substituted hydrazine provides pyrazolinone-fused heterocycle 6,which is brominated to provide bromopyrazole 7. The pyrazole-fusedheterocycles can also be similarly prepared with an aminoheteroaryl inplace of the aniline. For example, compound 12d (Table 7) is preparedstarting from 2-dimethylamino-4-methyl-5-amino pyridine (T. Ebara et al.JP54028330 [CAN 91:40904])

[0196] Intermediate bromopyrazole 7 is converted into the compounds ofFormulae I and I, as illustrated in Scheme 2 for Formula I, where R²,R³, R⁴, R^(d), R^(e), and n are as described above, and Ar, as describedabove, is for example phenyl optionally-substituted with one or moregroups X.

[0197] According to Scheme 2, intermediate bromopyrazole 7 is metallatedand reacted with an R^(d), R⁵_substituted aldehyde or ketone to providealcohol 8a which may be eliminated to the corresponding alkene 9. It isappreciated that depending upon the reaction conditions, and the natureof R^(d) and R⁵, the double bond stereochemistry resulting from theelimination reaction to alkene 9 may be either an E-double bond, aZ-double bond, or a mixture of both in various ratios. Subsequentreduction of alkene 9, by hydrogenation for example, provides alkane 10.It is understood that R^(e) as defined above corresponds to CH₂—R⁵ orCH—R⁵ of alcohol 8a or alkene 9, respectively. Alternatively,bromopyrazole 7 is metallated and reacted with an R^(d),R^(e)-substituted aldehyde or ketone to provide alcohol 8b which may bedeoxygenated, under radical conditions for example, to provide alkane10.

[0198] Alternatively, intermediate bromopyrazole 7 is converted into thecompounds of Formulae I and II, as illustrated in Scheme 3 for FormulaI, where R², R³, R⁴, R^(a), R^(b), and n are as described above, and Ar,as described above, is for example phenyl optionally-substituted withone or more groups X.

[0199] According to Scheme 3, intermediate bromopyrazole 7 is metallatedand reacted with carbon dioxide, or a carbon dioxide equivalent, toprovide carboxylic acid 11. Acid 11 is converted to the correspondingamine 13 via an amide rearrangement, such as by the Curtius, Lossen, orSchmidt reaction, or as illustrated in Scheme 3 by the Hofmann reactioninvolving intermediate carbamate 12. Amine 13 is converted into themono- or disubstituted amine 14 by reductive amination or successivereductive amination, respectively, using an appropriate aldehyde orketone, and a reducing agent, such as sodium cyanoborohydride, sodiumtriacetoxyborohydride, and the like. Alternatively, amine 13 isconverted into mono- or disubstituted amine 14 via acylation with anappropriate carboxlic acid derivative, such as the corresponding acidchloride, and reduction with an appropriate reducing agent such asdiborane, borane-THF complex, and the like. Another alternativeconversion of amine 13 to mono- or disubstituted amine 14 is viaalkylation with an appropriate alkylating agent, such as methyl iodide,ethyl bromide, and the like, optionally under basic conditions. It isappreciated that each substituent R^(a) and R^(b) may be introducedusing the same synthetic route described herein, or each substituent maybe introduced by a different synthetic route described herein.

[0200] Alternatively, intermediate carboxylic acid 11 is converted intothe compounds of Formulae I and II, as illustrated in Scheme 4 forFormula I, where R², R³, R⁴, R^(a), R^(b), and n are as described above,and Ar, as described above, is for example phenyl optionally-substitutedwith one or more groups X.

[0201] According to Scheme 4, intermediate acid 11 is converted into thecorresponding amide 15 and may be further reduced to amine 16.

[0202] Alternatively, pyrazolinone-fused heterocyclic 6 is convertedinto the compounds of Formulae I and II, as illustrated in Scheme 5 forFormula I, where R², R³, R⁴, R^(a), and n are as described above, andAr, as described above, is for example phenyl optionally-substitutedwith one or more groups X.

[0203] According to Scheme 5, intermediate pyrazolinone-fusedheterocycle 6 is converted into the corresponding alkoxypyrazole-fusedheterocycle 17.

[0204] Alternatively, intermediate bromopyrazole 7 is converted into thecompounds of Formulae I and II, as illustrated in Scheme 6 for FormulaI, where R², R³, R⁴, and n are as described above, and Ar, as describedabove, is for example phenyl optionally-substituted with one or moregroups X.

[0205] According to Scheme 6, intermediate bromopyrazole 7 is subjectedto a metal-catalyzed aryl coupling reaction to provide an aryl pyrazole,as illustrated by, for example phenyl pyrazole 18, optionallysubstituted with one or more groups Y.

[0206] It is understood that the synthetic routes illustrated in Schemes1-6 are suitable for preparing other compounds of Formulae I and II,including those compounds where Ar, as defined above, is for examplenaphthyl, pyrimidinyl, or pyridinyl, each of which may be optionallysubstituted. It is also appreciated that R² as pertains to theillustrative synthetic sequences of Schemes 1-6 may be a protectinggroup, as defined above, which may be conveniently removed to provide R²as hydrogen, or to introduce R² as alkyl, aryl, acyl, or alkylsulfonyl,as defined above.

Administration and Pharmaceutical Composition

[0207] The present invention includes pharmaceutical compositionscomprising at least one compound of the present invention, or anindividual isomer, racemic or non-racemic mixture of isomers or apharmaceutically acceptable salt or solvate thereof, together with atleast one pharmaceutically acceptable carrier, and optionally othertherapeutic and/or prophylactic ingredients.

[0208] In general, the compounds of the present invention will beadministered in a therapeutically effective amount by any of theaccepted modes of administration for agents that serve similarutilities. Suitable dosage ranges are typically 1-500 mg daily,preferably 1-100 mg daily, and most preferably 1-30 mg daily, dependingupon numerous factors such as the severity of the disease to be treated,the age and relative health of the subject, the potency of the compoundused, the route and form of administration, the indication towards whichthe administration is directed, and the preferences and experience ofthe medical practitioner involved. One of ordinary skill in the art oftreating such diseases will be able, without undue experimentation andin reliance upon personal knowledge and the disclosure of thisApplication, to ascertain a therapeutically effective amount of thecompounds of the present invention for a given disease.

[0209] In general, compounds of the present invention will beadministered as pharmaceutical formulations including those suitable fororal (including buccal and sub-lingual), rectal, nasal, topical,pulmonary, vaginal, or parenteral (including intramuscular,intraarterial, intrathecal, subcutaneous and intravenous) administrationor in a form suitable for administration by inhalation or insufflation.The preferred manner of administration is generally oral using aconvenient daily dosage regimen which can be adjusted according to thedegree of affliction.

[0210] A compound or compounds of the present invention, together withone or more conventional adjuvants, carriers, or diluents, may be placedinto the form of pharmaceutical compositions and unit dosages. Thepharmaceutical compositions and unit dosage forms may be comprised ofconventional ingredients in conventional proportions, with or withoutadditional active compounds or principles, and the unit dosage forms maycontain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed. Thepharmaceutical compositions may be employed as solids, such as tabletsor filled capsules, semisolids, powders, sustained release formulations,or liquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

[0211] The compounds of the present invention may be formulated in awide variety of oral administration dosage forms. The pharmaceuticalcompositions and dosage forms may comprise a compound or compounds ofthe present invention or pharmaceutically acceptable salts thereof asthe active component. The pharmaceutically acceptable carriers may beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier may be one or more substances which may alsoact as diluents, flavoring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier generally is a finelydivided solid which is a mixture with the finely divided activecomponent. In tablets, the active component generally is mixed with thecarrier having the necessary binding capacity in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from about one (1) to about seventy (70) percent ofthe active compound. Suitable carriers include but are not limited tomagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa bufter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier, providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is in association with it. Similarly,cachets and lozenges are included. Tablets, powders, capsules, pills,cachets, and lozenges may be as solid forms suitable for oraladministration.

[0212] Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizing, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

[0213] The compounds of the present invention may be formulated forparenteral administration (e.g., by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, for example solutions in aqueous polyethylene glycol. Examplesof oily or nonaqueous carriers, diluents, solvents or vehicles includepropylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil),and injectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilisation from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

[0214] The compounds of the present invention may be formulated fortopical administration to the epidermis as ointments, creams or lotions,or as a transdermal patch. Ointments and creams may, for example, beformulated with an aqueous or oily base with the addition of suitablethickening and/or gelling agents. Lotions may be formulated with anaqueous or oily base and will in general also containing one or moreemulsifying agents, stabilizing agents, dispersing agents, suspendingagents, thickening agents, or coloring agents. Formulations suitable fortopical administration in the mouth include lozenges comprising activeagents in a flavored base, usually sucrose and acacia or tragacanth;pastilles comprising the active ingredient in an inert base such asgelatin and glycerin or sucrose and acacia; and mouthwashes comprisingthe active ingredient in a suitable liquid carrier.

[0215] The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

[0216] The compounds of the present invention may be formulated forvaginal administration. Pessaries, tampons, creams, gels, pastes, foamsor sprays containing in addition to the active ingredient such carriersas are known in the art to be appropriate.

[0217] The compounds of the present invention may be formulated fornasal administration. The solutions or suspensions are applied directlyto the nasal cavity by conventional means, for example, with a dropper,pipette or spray. The formulations may be provided in a single ormultidose form. In the latter case of a dropper or pipette, this may beachieved by the patient administering an appropriate, predeterminedvolume of the solution or suspension. In the case of a spray, this maybe achieved for example by means of a metering atomizing spray pump.

[0218] The compounds of the present invention may be formulated foraerosol administration, particularly to the respiratory tract andincluding intranasal administration. The compound will generally have asmall particle size for example of the order of five (5) microns orless. Such a particle size may be obtained by means known in the art,for example by micronization. The active ingredient is provided in apressurized pack with a suitable propellant such as a chlorofluorocarbon(CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

[0219] When desired, formulations can be prepared with enteric coatingsadapted for sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to a skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylaza-cycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into to the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

[0220] The pharmaceutical preparations are preferably in unit dosageforms. In such form, the preparation is subdivided into unit dosescontaining appropriate quantities of the active component. The unitdosage form can be a packaged preparation, the package containingdiscrete quantities of preparation, such as packeted tablets, capsules,and powders in vials or ampoules. Also, the unit dosage form can be acapsule, tablet, cachet, or lozenge itself, or it can be the appropriatenumber of any of these in packaged form.

[0221] Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described in Example 2.

EXAMPLES

[0222] The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

[0223] Efforts have been made to ensure accuracy with respect to numbersused (e.g., amounts, temperatures), but allowance for some experimentalerror and deviation, including differences in calibration, rounding ofnumbers, and the like, is contemplated.

Example 13-Bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine

[0224]

[0225] Step 1:

[0226] 5-Chloropentanoic Acid (2-chloro-4,6-dimethylphenyl)amide

[0227] To a solution of 2-chloro-4,6-dimethylaniline (14.7 g) anddiisopropylethylamine (18 mL) in 150 mL of THF, was added a solution of5-chlorovaleryl chloride (12.2 mL) in 75 mL of THF. After the reactionmixture had been allowed to stir at room temperature overnight, it wasfiltered and the filtrate concentrated on the rotary evaporator. Theresidue was dissolved in ethyl acetate and washed with 1 M aqueous HCl,saturated aqueous sodium bicarbonate, and brine. The ethyl acetatesolution was then dried with magnesium sulfate and concentrated on therotary evaporator to give a solid which was combined with a 1:1 mixtureof hexane and diethyl ether. After this mixture had been stirred for anhour, it was filtered and the collected solids were dried to provide12.2 g of 5-chloropentanoic acid (2-chloro-4,6-dimethylphenyl)amide, mp80.6-82.9° C.

[0228] Step 2:

[0229] 1-(2-Chloro-4,6-dimethylphenylpiperidin-2-one

[0230] 5-Chloropentanoic acid (2-chloro-4,6-dimethylphenyl)amide (21.7g), potassium t-butoxide (9.34 g), and sodium iodide (1.2 g) werecombined in 200 mL t-butanol and the mixture was stirred in a 60° C. oilbath for 3 h. After cooling to room temperature, the reaction mixturewas partitioned between ethyl acetate and water. The aqueous phase waswashed with additional ethyl acetate. The organic phases were washedwith brine, dried with magnesium sulfate, and concentrated to give 18.9g of 1-(2-chloro-4,6-dimethylphenyl)piperidin-2-one as a solid, mp.107.7-108.7° C.

[0231] Step 3:

[0232] 1-(2-Chloro-4,6-dimethylphenyl)piperidine-2-thione

[0233] 1-(2-Chloro-4,6-dimethylphenyl)piperidin-2-one (18.8 g) andLawesson's reagent[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide](19.2 g) were combined in 150 mL toluene and the mixture was stirred inan 80° C. oil bath for 3 h. The reaction mixture was then cooled to roomtemperature and filtered. The filtrate was concentrated on the rotaryevaporator and the residue was chromatographed on silica gel, elutingwith 9:1 hexane/acetone, to provide 19.4 g of1-(2-chloro-4,6-dimethylphenyl)piperidine-2-thione, mp 146.8-148.0° C.

[0234] Step 4:

[0235]1-(2-Chloro-4,6-dimethylphenyl)-2-methylsulfanyl-1,4,5,6-tetrahydropyridine-3-carboxylicAcid Methyl Ester

[0236] 1-(2-Chloro-4,6-dimethylphenyl)piperidine-2-thione (5.11 g),dimethyl carbonate (17.0 mL), sodium hydride (3.7 g of a 60% dispersionin mineral oil), and methanol (0.5 mL) were combined in 100 mL ofdioxane and the mixture was stirred in a 120° C. oil bath for 4 h. Afterthe reaction had cooled to room temperature, it was quenched by theaddition of aqueous ammonium chloride, diluted with water and washedtwice with ethyl acetate. After drying over magnesium sulfate, the ethylacetate was concentrated and the residue chromatographed on silica gelusing an acetone/hexane gradient to provide 5.00 g1-(2-chloro-4,6-dimethylphenyl)-2-methylsullfanyl-1,4,5,6-tetrahydropyridine-3-carboxylicacid methyl ester, mp 85.3-87.6° C.

[0237] Step 5:

[0238]7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo-[3,4-b]pyridin-3-one

[0239]1-(2-Chloro-4,6-dimethylphenyl)-2-methylsulfanyl-1,4,5,6-tetrahydropyridine-3-carboxylicacid methyl ester (4.99 g), methylhydrazine (16.4 mL), p-toluenesulfonicacid monohydrate (2.91 g), and methanol (75 mL) were combined in a glassvessel sealed with a Telfon™ screw cap. The reaction mixture was stirredin a 130° C. oil bath for 24 h, then cooled to room temperature andconcentrated on the rotary evaporator. The residue was chromatographedon silica gel using a methanol/dichloromethane gradient to give 3.21 gof7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo-[3,4-b]pyridin-3-one,mp 95.9-99.9° C.

[0240] Step 6:

[0241]3-Bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine

[0242]7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one(3.16 g) and phosphorus oxybromide (15.5 g) were combined and stirred ina 110° C. oil bath for 4 h. After the reaction mixture had cooled toroom temperature, it was dissolved in dichloromethane and added to 200mL of ice/water. This mixture was stirred vigorously for 30 min. Thephases were then separated and the aqueous phase was washed withadditional dichloromethane. The combined organic phases were washed withaqueous sodium bicarbonate, dried with magnesium sulfate, andconcentrated on the rotary evaporator. The residue was chromatographedon silica gel eluting with an acetone/hexane gradient to provide 1.16 gof3-bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine,mp 106-107° C.

Example 23-Bromo-7-(2,4-dichlorophenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine

[0243]

[0244] Example 2 was prepared according the procedure described inExample 1, except that 2-chloro-4,6-dimethylaniline was replaced by2,4-dichloroaniline in step 1, and step 4 was performed as follows:

[0245]1-(2,4-Dichlorophenyl)-2-methylsulfanyl-1,4,5,6-tetrahydropyridine-3-carboxylicAcid Methyl Ester

[0246] To 39.6 ml of a 3M solution ethylmagnesium bromide in ether wasadded 100 mL of dry tetrahydrofuran under an atmosphere of nitrogen.Then 16.7 mL of diisopropylamine was added dropwise. The reactionmixture was then heated to 80° C. for 1 h. After cooling to roomtemperature, the mixture was treated with a solution of 6.19 g of1-(2,4-dichlorophenyl)piperidine-2-thione in 50 mL of drytetrahydrofuran, heated to 80° C. for 30 min, and cooled again to roomtemperature. Then the mixture was treated dropwise with 10.0 mL ofdimethylcarbonate and heated to 80° C. for 26 h. After cooling to roomtemperature, 100 g of ice was added along with 150 mL of 1.2M HCl. Themixture was extracted three times with 100 mL portions ofdichloromethane. The combined organic extracts were washed with 100 mLof brine, dried over magnesium sulfate, concentrated, and then keptunder high vacuum at 50° C. to remove the higher boiling volatilematerials. The residue was purified by flash silica gel chromatographyusing 7% acetone/hexane as solvent yielding 5.25 g of1-(2,4-dichlorophenyl)-2-methylsulfanyl-1,4,5,6-tetrahydropyridine-3-carboxylicacid methyl ester as a yellow solid, mp 83-86° C.

Examples 3-4

[0247] Example 3 was prepared according to the procedure described inExample 1, except that 2-chloro-4,6-dimethylaniline was replaced by2,4,6-trimethylaniline in step 1.

[0248] Example 4 was prepared according the procedure described inExample 1, except that 2-chloro-4,6-dimethylaniline was replaced by2,4,6-trimethylaniline, and 5-chlorovaleryl chloride was replaced by6-chlorocaproyl chloride in step 1. TABLE 1 Compounds prepared inExamples 1-4. MH+ mp observed Example Structure Name (° C.) (predicted)1

3-Bromo-7-(2-chloro-4,6- dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H- pyrazolo[3,4-b]pyridine 106-107 354 (354) 2

3-Bromo-7-(2,4-dichloro-phenyl)-2- methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine 360 (360) 3

3-Bromo-2-methyl-7-(2,4,6- trimethyl-phenyl)-4,5,6,7- tetrahydro-2H-pyrazolo[3,4-b]pyridine 94.6-97.9 334 (334) 4

3-Bromo-2-methyl-8-(2,4,6- trimethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,8-triaza-azulene 348 (348)

Example 5a4-[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo-[3,4-b]pyridin-3-yl]heptan-4-ol

[0249]

[0250]3-Bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine(122 mg) and a crystal of 1,10-phenanthroline were dissolved in 3 mL ofdry tetrahydrofuran and the solution was chilled to −78° C. under anatmosphere of argon. Then n-butyllithium (2.0 M in cyclohexane) wasadded until the dark color of the organolithium/phenanthroline complexpersisted. An additional 0.17 mL of the butyllithium solution then wasadded. After 10 min, a solution of 4-heptanone (42.6 mg) in 1 mLtetrahydrofuran was added via syringe. The reaction mixture was allowedto stir at −78° C. for 15 min, then was allowed to warm to 0° C. Afterquenching with aqueous ammonium chloride, the reaction mixture waspartitioned between ethyl acetate and brine. The ethyl acetate was driedwith magnesium sulfate and concentrated on the rotary evaporator. Theresidue was chromatographed on silica gel eluting with 9:1hexane/acetone to provide 76.0 mg of4-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo-[3,4-b]pyridin-3-yl]heptan-4-ol,which was recrystallized from hexane, mp 129-130° C.

Examples 5b-5m

[0251] Example 5b was prepared according to the procedure described inExample 5a, except that the compound from Example 1 was replaced withthe compound from Example 3.

[0252] Example 5c was prepared according to the procedure described inExample 5a, except that 4-heptanone was replaced with 1-thienylbutanoneand the compound from Example 1 was replaced with the compound fromExample 3.

[0253] Example 5d was prepared according to the procedure described inExample 5a, except that the compound from Example 1 was replaced withthe compound from Example 4.

[0254] Example 5e was prepared according to the procedure described inExample. 5a, except that the compound from Example 1 was replaced withthe compound from Example 2.

[0255] Example 5f was prepared according to the procedure described inExample 5a, except that 4-heptanone was replaced with1,3-bismethoxypropan-2-one and the compound from Example 1 was replacedwith the compound from Example 3.

[0256] Example 5g was prepared according to the procedure described inExample 5a, except that 4-heptanone was replaced with1,4-bismethoxybutan-2-one and the compound from Example 1 was replacedwith the compound from Example 3.

[0257] Example 5h was prepared according to the procedure described inExample 5a, except that 4-heptanone was replaced with1-thiazol-2-ylpropanone and the compound from Example 1 was replacedwith the compound from Example 3.

[0258] Example 5i was prepared according to the procedure described inExample 5a, except that 4-heptanone was replaced with2-furancarboxaldehyde and the compound from Example 1 was replaced withthe compound from Example 3.

[0259] Example 5j was prepared according to the procedure described inExample 5a, except that 4-heptanone was replaced with propanal and thecompound from Example 1 was replaced with the compound from Example 3.

[0260] Example 5k was prepared according to the procedure described inExample 5a, except that 4-heptanone was replaced with1-(1-ethylimidazol-2-yl)butanone and the compound from Example 1 wasreplaced with the compound from Example 3.

[0261] Example 51 was prepared according to the procedure described inExample 5a, except that 4-heptanone was replaced withtetrahydropyran-4-one and the compound from Example 1 was replaced withthe compound from Example 3.

[0262] Example 5m was prepared according to the procedure described inExample 5a, except that 4-heptanone was replaced with water. TABLE 2Compounds prepared in Examples 5. MH+ mp observed Example Structure Name(° C.) (predicted) 5a

4-[7-(2-Chloro-4,6-dimethylphenyl)- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan- 4-ol 129-130 390 (390) 5b

4-[2-Methyl-7-(2,4,6- trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3- yl]heptan-4-ol   126-127.9 370 (370) 5c

1-[2-Methyl-7-(2,4,6- trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-1- thiophen-2-ylbutan-1-ol 175.9-178.4410 (410) 5d

4-[2-Methyl-8-(2,4,6- trimethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,8-triazaazulen-3- yl]heptan-4-ol   87-91.1 384 (384) 5e

4-[7-(2,4-Dichlorophenyl)-2-methyl- 4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan- 4-ol 121.4-122.6 396 (396) 5f

1,3-Dimethoxy-2-[2-methyl-7-(2,4,6- trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3- yl]propan-2-ol 120.3-121.8 374 (374) 5g

1,4-Dimethoxy-2-[2-methyl-7-(2,4,6- trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3- yl]butan-2-ol 107.9-110.9 388 (388) 5h

1-[2-Methyl-7-(2,4,6- trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-1- thiazol-2-ylbutan-1-ol 160.1-165.6411 (411) 5i

Furan-2-yl[2-methyl-7-(2,4,6- trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridin-3-yll9 methanol 163.1-174.4 352(352) 5j

1-[2-Methyl-7-(2,4,6- trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3- yl]propan-1-ol 179.4-180.9 314 (314) 5k

1-(1-Ethyl-1H-imidazol-2-yl)-1-[2- methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridin-3-yl]butan-1-ol 94.9-100.9 422 (422) 5l

4-[2-Methyl-7-(2,4,6- trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3- yl]tetrahydropyran-4-ol   193-195.1 356(356) 5m

7-(2-Chloro-4,6-dimethylphenyl)-2- methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine 97-98 276 (276)

Example 6a7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine

[0263]

[0264]4-[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-ol(594 mg) and p-toluenesulfonic acid monohydrate (74 mg) were combined in13 mL toluene and the stirred mixture was heated to 110° C. for 11 h.The reaction mixture was then cooled to room temperature and partitionedbetween ethyl acetate and aqueous sodium bicarbonate. The aqueous phasewas washed with additional ethyl acetate. The combined ethyl acetate waswashed with brine, dried with magnesium sulfate, and concentrated. Theresidue was chromatographed on silica gel eluting with an acetone/hexanegradient to provide 461 mg of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine,which was recrystallized from hexane, mp 86.7-88.2° C.

Examples 6b-6f

[0265] Example 6b was prepared according to the procedure described inExample 6a, except that4-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-olwas replaced by the compound from Example 5b.

[0266] Example 6c was prepared according to the procedure described inExample 6a, except that4-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-olwas replaced by the compound from Example 5c.

[0267] Example 6d was prepared according to the procedure described inExample 6a, except that4-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-olwas replaced by the compound from Example 5d.

[0268] Example 6e was prepared according to the procedure described inExample 6a, except that4-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-olwas replaced by the compound from Example 5e.

[0269] Example 6f was prepared according to the procedure described inExample 6a, except that4-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-olwas replaced by the compound from Example 5h. TABLE 3 Compounds preparedin Examples 6. MH+ mp observed Example Structure Name (° C.) (predicted)6a

7-(2-Chloro-4,6-dimethylphenyl)- 2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H- pyrazolo[3,4-b]pyridine 86.7-88.2 372 (372) 6b

2-Methyl-3-(1-propylbut-1-enyl)-7- (2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridine 101.6-102.6 352 (352) 6c

2-Methyl-3-(1-thiophen-2-ylbut-1- enyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H- pyrazolo[3,4-b]pyridine oil 392 (392) 6d

2-Methyl-3-(1-propylbut-1-enyl)-8- (2,4,6-trimethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,8- triazaazulene 101.9-103.9 366 (366) 6e

7-(2,4-Dichlorophenyl)-2-methyl-3- (1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridine oil 378 (378) 6f

2-Methyl-3-(1-thiazol-2-ylbut-1- enyl)-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H- pyrazolo[3,4-b]pyridine 393 (393)

EXAMPLE 7a

[0270]7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine

[0271]7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine(41.5 mg) was dissolved in acetic acid (1 mL) and 12 mg of 10% palladiumon carbon was added. The mixture was stirred under hydrogen at oneatmosphere for 12 h. The mixture was diluted with ethyl acetate andfiltered through diatomaceous earth which was then washed with ethylacetate. The ethyl acetate filtrate was washed with aqueous sodiumbicarbonate, dried with magnesium sulfate, and concentrated. The residuewas chromatographed on silica gel eluting with an acetone/hexanegradient to provide 10.2 mg of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine,as a crystalline film, ms m/z 374 (MH⁺).

Examples 7b-7d

[0272] Example 7b was prepared according to the procedure described inExample 7a, except that7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridinewas replaced by the compound from Example 6b.

[0273] Example 7c was prepared according to the procedure described inExample 7a, except that7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridinewas replaced by the compound from Example 6c.

[0274] Example 7d was prepared according to the procedure described inExample 7a, except that7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridinewas replaced by the compound from Example 6d. TABLE 4 Compounds preparedin Examples 7. mp observed Example Structure Name (° C.) (predicted) 7a

7-(2-Chloro-4,6-dimethylphenyl)-2- methyl-3-(1-propylbutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridine 374 (374) 7b

2-Methyl-3-(1-propylbutyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro- 2H-pyrazolo[3,4-b]pyridine91.5-92   354 (354) 7c

2-Methyl-3-(1-thiophen-2-ylbutyl)-7- (2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridine 87.6-90.3 394 (394) 7d

2-Methyl-3-(1-propylbutyl)-8-(2,4,6- trimethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,8-triazaazulene 96.0-98.1 368 (368)

Example 8a7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4V5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicAcid

[0275]

[0276]3-Bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine(1.46 g) and a few crystals of 1,10 phenanthroline were dissolved in 25mL of dry tetrahydrofuran and chilled to −78° C. under an atmosphere ofargon. Then a 2.0 M solution of n-butyllithium in cyclohexane was addeddropwise until the dark color of the phenanthroline/organolithiumcomplex persisted. Then an additional 2.05 mL of the n-butyllithiumsolution was added. After 10 minutes, carbon dioxide, generated from dryice, was bubbled through the reaction mixture for 5 minutes. After thereaction mixture had been stirred at −78° C. for 5 minutes, the coolingbath was removed and the mixture was allowed to warm for 5 minutesbefore being quenched by the addition of water. The mixture was combinedwith ethyl acetate and water, acidified with dilute hydrochloric acid,and the phases separated. The ethyl acetate was dried with magnesiumsulfate and concentrated. The residue was chromatographed on silica geleluting with an acetone/hexane gradient to provide 1.11 g of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicacid, mp 247.8-248.3° C.

Example 8b7-(2,4,6-Trimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicAcid

[0277] Example 8b was prepared according to the procedure described inExample 8a, except that3-bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridinewas replaced by the compound from Example 3.

Example 8c[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]carbamicAcid Tert-Butyl Ester

[0278]

[0279] A 159 mg sample of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicacid was combined with 2.5 mL of t-butanol and 140 mL of triethylaminewas added. Then 129 μL of diphenylphosphoryl azide was added and thereaction mixture was heated to 85° C. for 2 h. After cooling to roomtemperature, the reaction mixture was dissolved in ethyl acetate andwashed with 1 M aqueous sodium bisulfate, aqueous sodium bicarbonate,water, and brine. The ethyl acetate solution was dried with magnesiumsulfate and concentrated to give material which was chromatographed onsilica gel eluting with an acetone/hexane gradient. Product containingfractions were concentrated to give a solid residue which was slurriedin a small amount of boiling hexane. After the mixture cooled to roomtemperature, the solids were collected by filtration to provide 71 mg of[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]carbamicacid tert-butyl ester, mp 171.4-175.7° C.

Example 8d

[0280] Example 8d was prepared according to the procedure described inExample 8c, except that t-butanol was replaced by ethanol.

Example 9a[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]dipropylamine

[0281]

[0282] Step 1:

[0283]7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine

[0284] To a 0° C. solution of 287 mg of[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]carbamicacid tert-butyl ester (Example 8c) in 9 mL of dichloromethane, was added3 mL of trifluoroacetic acid. After 15 min, the cooling bath was removedand the reaction mixture was allowed to stir and warm to roomtemperature during 3 h. The reaction mixture was then diluted withdichloromethane and washed with dilute aqueous sodium hydroxide. Theaqueous phase was washed with additional dichloromethane, after whichthe combined organics were dried with magnesium sulfate andconcentrated. The residue was chromatographed on silica gel eluting witha methanol/dichloromethane gradient to provide 182 mg of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine,mp 234-236° C.

[0285] Step 2:

[0286][7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]dipropylamine

[0287] To a solution of 55 mg of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylaminein 3 mL of dichloroethane was added 29 μL of propionaldehyde followed afew minutes later by 124 mg of sodium triacetoxyborohydride. Thereaction mixture was stirred at room temperature for 2 d, during whichtime an additional 30 mL of propionaldehyde and an additional 62 mg ofsodium triacetoxyborohydride were added to drive the reaction tocompletion. The mixture was then diluted with dichloromethane and washedwith dilute aqueous sodium hydroxide. The organics were dried overmagnesium sulfate and concentrated. The residue was chromatographed onsilica gel eluting with an acetone/hexane gradient to provide a solidwhich was recrystallized from hexane to give 17 mg of[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]dipropylamine,mp 90-91° C.

Example 9b

[0288] Example 9b was prepared according to the procedure described inExample 9a, except that step 2 was performed as follows:

[0289] Step 2:

[0290][7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl](1-propylbutyl)amine

[0291]7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine(45.7 mg) and 4-heptanone (24 mL) were dissolved and stirred in 3 mL ofdichloroethane. After 15 min, 44.5 mg of sodium triacetoxyborohydridewas added. The reaction mixture was stirred at 60° C. during the day andat room temperature over night during 3 d. During this period, anadditional 109μL of 4-heptanone and an additional 104 mg of sodiumtriacetoxyborohydride were added to drive the reaction to completion.The reaction mixture was then partitioned between ethyl acetate andwater. The ethyl acetate was dried with magnesium sulfate andconcentrated. The crude product was chromatographed on silica geleluting with an acetone/hexane gradient to provide 11 mg of[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl](1-propylbutyl)amineas a crystalline film, ms m/z 389 (MH⁺).

Example 9c[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]furan-2-ylmethylpropylamine

[0292]

[0293] Step 1:

[0294]N-[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propionamide

[0295] To a stirred solution of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine(0.51 g) and triethylamine (0.27 mL) in dichloromethane (40 mL) at 0° C.was added propionyl chloride (0.17 mL) in dichloromethane (10 mL)dropwise over 25 minutes. The resulting mixture was stirred for anadditional 1 hour at 0° C., followed by 14 hours at room temperature.The reaction mixture was then stirred with an aqueous 5% citric acidsolution (40 mL) for 10 minutes. The layers were separated, and theaqueous layer was further extracted with dichloromethane (50 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate, thendecanted from the desiccating agent and concentrated under reducedpressure. The resulting residue was purified by silica gelchromatography using a dichloromethane/methanol gradient to affordN-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propionamide(0.49 g) as an off white solid, ms m/z 347 (MH⁺).

[0296] Step 2:

[0297][7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propylamine

[0298] To a stirred, chilled (0° C.) solution ofN-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propionamide(0.48 g) in tetrahydrofuran (9 mL), under nitrogen, was added borane-THFcomplex (4.1 mL of a 1.0 M tetrahydrofuran solution) in one portion. Theresulting mixture was stirred for 1 hour at 0° C., then stirred for 48hours at room temperature. The reaction mixture was then treated with1:2 acetic acid/ethyl acetate (11 mL), mixed briefly, and allowed tostand at room temperature for 24 hours. The resulting mixture was addedto a 3% aqueous sodium hydroxide solution (75 mL), and extracted withethyl acetate (3×75 mL). The combined organic extracts were dried overanhydrous sodium sulfate, then decanted from the desiccating agent andconcentrated under reduced pressure to provide, without furtherpurification,[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propylamine(0.45 g), as a pale yellow solid, ms m/z333 (MH⁺).

[0299] Step 3:

[0300][7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]furan-2-ylmethylpropylamine

[0301][7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propylamine(17 mg) was treated with a solution of 2-furancarboxaldehyde (9 mg) in1,2-dichloroethane (0.38 mL). To the resulting mixture was then addedacetic acid (15 mg), followed by sodium triacetoxyborohydride (30 mg).At room temperature, the resulting mixture was agitated for 72 hoursusing a rotary shaker. The reaction mixture was then treated withsaturated aqueous sodium bicarbonate (2 mL) and extracted with ethylacetate (3×2 mL). The combined organic extracts were then concentratedunder reduced pressure. The resulting orange-yellow residue was purifiedby preparative high-pressure liquid chromatography (HPLC) onreversed-phase (C18) silica gel (gradient, acetonitrile-0.1%trifluoroacetic acid=10:90 to 90:10) to afford[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]furan-2-ylmethylpropylamine,trifluoroacetate salt (5 mg) as a yellow solid, ms m/z 413 (MH⁺).

Examples 9d-9ai

[0302] Example 9d was prepared according to the procedure described inExample 9c, except that 2-furancarboxaldehyde was replaced bypyridine-2-carboxaldehyde in step 3.

[0303] Example 9e was prepared according to the procedure described inExample 9c, except that 2-furancarboxaldehyde was replaced bypyridine-4-carboxaldehyde in step 3.

[0304] Example 9f was prepared according to the procedure described inExample 9c, except that 2-furancarboxaldehyde was replaced byimidazole-2-carboxaldehyde in step 3.

[0305] Example 9g was prepared according to the procedure described inExample 9c, except that 2-furancarboxaldehyde was replaced bypyridine-3-carboxaldehyde in step 3.

[0306] Example 9h was prepared according to the procedure described inExample 9c, except that 2-furancarboxaldehyde was replaced byimidazole-4-carboxaldehyde in step 3.

[0307] Example 9i was prepared according to the procedure described inExample 9c, except that 2-furancarboxaldehyde was replaced by3,4,5-trimethoxybenzaldehyde in step 3.

[0308] Example 9j was prepared according to the procedure described inExample 9c, except that 2-furancarboxaldehyde was replaced by2,3,4-trimethoxybenzaldehyde in step 3.

[0309] Example 9k was prepared according to the procedure described inExample 9c, except that 2-furancarboxaldehyde was replaced by1-methylimidazole-4-carboxaldehyde in step 3.

[0310] Example 91 was prepared according to the procedure described inExample 9c, except that 2-furancarboxaldehyde was replaced by3-methylimidazole-4-carboxaldehyde in step 3.

[0311] Examples 9m⁻⁹ae and 9ai in Table 5 were prepared by reductiveamination as described in step 3 of Example 9c with the appropriatesecondary amines and aldehyde. The secondary amines were prepared byreduction of amides 10c and 10d (Table 6) as described in step 2 ofExample 9c.

Example 9af(1-Methoxymethylpropyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amine

[0312]

[0313] 2-Methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine(101 mg, 0.373 mmol) was dissolved in CH₂Cl₂ (2 mL). Et₃N (0.25 mL, 1.79mmol) and the 1-methoxy-butan-2-one (65 mg, 0.636 mmol) were added atroom temperature. A solution of TiCl₄ in toluene (1 M; 0.35 mL, 0.35mmol) was added dropwise via syringe. The mixture was then stirred atroom temperature overnight. NaCNBH₃ (120 mg, 1.9 mmol) in methanol (1mL) was added slowly. The stirring continued at room temperature for 0.5h and the reaction was quenched by the addition of 2 N NaOH (2 mL).EtOAc was added and the layers were separated.

[0314] The organic layer was washed with water, brine and dried overMgSO₄ The solvent was removed and the residue purified by chromatographyon SiO₂, (gradient elution: 2% MeOH in CH₂Cl₂ containing 0.1% NH₄OH to3% MeOH in CH₂Cl₂ containing 0.15% NH₄OH over 20 minutes) to yield 102mg of product (0.286 mmol; 77%).

[0315] Examples 9ag, 9ah, 9aj and 9ak were prepared in analogous fashionusing 3-pentanone, 1,3-dimethoxypropan-2-one, and1,4-dimethoxypentan-2-one.

[0316] Example 9al was prepared using the appropriate methodologydescribed hereinabove to prepare propyl7-(2,4,6-trimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylaminewhich is reacted with phenylsulfonyl chloride utilizing Schotten-Baumanconditions. TABLE 5 Compounds prepared in Examples 8-9. MH+ mp observedExample Structure Name (° C.) (predicted) 8a

7-(2-Chloro-4,6-dimethylphenyl)- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3- carboxylic acid 247.8-248.3 320 (320) 8b

7-(2,4,6-Trimethylphenyl)-2- methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3- carboxylic acid 228.6-233.9 300 (300) 8c

[7-(2-Chloro-4,6-dimethylphenyl)- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3- yl]carbamic acid tert-butyl ester 171.4-175.7391 (391) 8d

[7-(2-Chloro-4,6-dimethylphenyl- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3- yl]carbamic acid ethyl ester 204.0-207.8 363(363) 9a

[7-(2-Chloro-4,6-dimethylphenyl)- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3- yl]dipropylamine 90-91 375 (375) 9b

[7-(2-Chloro-4,6-dimethylphenyl)- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl](1- propylbutyl)amine 389 (389) 9c

[7-(2-Chloro-4,6-dimethyl-phenyl)- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-furan- 2-ylmethyl-propyl-aminetrifluoroacetic acid salt 413 (413) 9d

[7-(2-Chloro-4,6-dimethyl-phenyl)- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propyl- pyridin-2-ylmethyl-aminetrifluoroacetic acid salt 424 (424) 9e

[7-(2-Chloro-4,6-dimethyl-phenyl)- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propyl- pyridin-4-ylmethyl-aminetrifluoroacetic acid salt 424 (424) 9f

[7-(2-Chloro-4,6-dimethyl-phenyl)- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-(1H- imidazol-2-ylmethyl)-propyl-aminetrifluoroacetic acid salt 413 (413) 9g

[7-(2-Chloro-4,6-dimethyl-phenyl)- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propyl- pyridin-3-ylmethyl-aminetrifluoroacetic acid salt 424 (424) 9h

[7-(2-Chloro-4,6-dimethyl-phenyl)- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-(1H- imidazol-4-ylmethyl)-propyl-aminetrifluoroacetic acid salt 413 (413) 9i

[7-(2-Chloro-4,6-dimethyl-phenyl)- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propyl- (3,4,5-trimethoxy-benzyl)-aminetrifluoroacetic acid salt 513 (513) 9j

[7-(2-Chloro-4,6-dimethyl-phenyl)- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propyl- (2,3,4-trimethoxy-benzyl)-aminetrifluoroacetic acid salt 513 (513) 9k

[7-(2-Chloro-4,6-dimethyl-phenyl)- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-(1- methyl-1H-imidazol-4-ylmethyl-propyl-amine trifluoroacetic acid salt 427 (427) 9l

[7-(2-Chloro-4,6-dimethyl-phenyl)- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-(3- methyl-3H-imidazol-4-ylmethyl)-propyl-amine trifluoroacetic acid salt 427 (427) 9m

(2-Methoxy-ethyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]thiazol-2- ylmethylamine, trifluoroaceticacid salt 426 (426) 9n

Furan-2-ylmethyl-(2-methoxy-ethyl)-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3- yl]amine, trifluoroacetic acidsalt 409 (409) 9o

(2-Methoxyethyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-(3,4,5- trimethoxy-benzyl)amine,trifluoroacetic acid salt 509 (509) 9p

4-({(2-Methoxyethyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H- pyrazolo[3,4-b]pyridin-3-yl]amino}methyl)benzonitrile, trifluoroacetic acid salt 444 (444) 9q

(2-Methoxyethyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propylamine, trifluoroacetic acid salt 371(371) 9r

(3,4-Dimethoxybenzyl)-(2-methoxyethyl)-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridin-3-yl]-amine,trifluoroacetic acid salt 479 (479) 9s

Cyclopropylmethyl-(2- methoxyethyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7- tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amine oil 383 (383) 9t

Benzyl-(2-methoxyethyl)-[2-methyl-7- (2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3- yl]-amine, trifluoroacetic acidsalt 419 (419) 9u

Butyl-(2-methoxyethyl)-[2-methyl-7- (2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3- yl]-amine, trifluoroacetic acidsalt 385 (385) 9v

[2-Methyl-7-(2,4,6-trimethylphenyl)- 4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propylthiazol-2- ylmethylamine, trifluoroacetic acidsalt 410 (410) 9w

4-({[2-Methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propylamino}-methyl)- benzonitrile, trifluoroacetic acidsalt 428 (428) 9x

(3,4-Dimethoxybenzyl)-[2-methyl- 7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridin-3-yl]-propylamine, trifluoroaceticacid salt 463 (463) 9y

Cyclopropylmethyl-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propylamine, trifluoroacetic acid salt 367(367) 9z

Benzyl-[2-methyl-7-(2,4,6- trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propylamine, trifluoroacetic acid salt 403(403) 9aa

Butyl-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridin-3-yl]-propylamine,trifluoroacetic acid salt 369 (369) 9ab

[2-Methyl-7-(2,4,6-trimethylphenyl)- 4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propylthiophen-2- ylmethylamine, trifluoroacetic acidsalt 409 (409) 9ac

Ethyl-(2-methoxyethyl)-[2-methyl- 7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridin-3-yl]-amine oil 357 (357) 9ad

Ethyl-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridin-3-yl]-propylamine oil 341(341) 9ae

[2-Methyl-7-(2,4,6-trimethylphenyl)- 4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-dipropylamine 88.9-91.5 355 (355) 9af

(1-Ethylpropyl)-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amine  99.3-104.9 341 (341) 9ag

(2-Methoxy-1-methoxymethylethyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3- yl]-amine oil 373 (373) 9ah

(3-Methoxy-1-methoxymethylpropyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3- yl]-amine oil 387 (387) 9ai

Cyclopropylmethyl-(2-methoxyethyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3- yl]-amine oil 383 (383) 9aj

(1-Methoxymethylpropyl)-[2-methyl-7- (2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3- yl]-amine  96.5-102.5 357 (357)9ak

(1-Methoxymethylbutyl)-[2-methyl- 7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridin-3-yl]-amine 100.1-104.4 371 (371)9al

N-[2-Methyl-7-(2,4,6- trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridin-3-yl]-N- propylbenzenesulfonamide,trifluoroacetic acid salt 453 (453)

EXAMPLE 10a7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicacid cyclopropylmethylpropylamide

[0317]

[0318]7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicacid (107.0 mg), 1-hydroxybenzotriazole hydrate (50.3 mg),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (72.5 mg),triethylamine (93 μL), and N-propylcyclopropanemethylamine (49 μL) werecombined in 4 mL of dichloromethane and stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetateand 1 M hydrochloric acid. The ethyl acetate solution was washed withaqueous sodium bicarbonate, dried with magnesium sulfate, andconcentrated. The crude product was chromatographed on silica geleluting with an acetone/hexane gradient giving a solid.Recrystallization from hexane provided 75.6 mg of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicacid cyclopropylmethylpropylamide, mp 120.6-122.0° C.

Example 10b(3,4-Dihydro-1H-isoguinolin-2-yl)[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]methanone

[0319]

[0320] A suspension of 125 mg of2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicacid in 5 mL of dichloromethane was treated with 116 μL oftriethylamine, 56 mg of 1-hydroxybenzotriazole hydrate, 88 mg of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, and 52 μLof 1,2,3,4-tetrahydroisoquinoline and stirred under an atmosphere ofnitrogen at room temperature for 20 h. The mixture was diluted with 50mL of ethyl acetate, washed with 30 mL of 0.5M HCl, washed with 30 mL ofsaturated sodium bicarbonate solution, dried over magnesium sulfate, andevaporated to dryness yielding 149 mg of(3,4-dihydro-1H-isoquinolin-2-yl)[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]methanone,mp 80.3-87.7° C.

[0321] Example 10c was prepared by acylation of2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine(prepared from example 8b using procedures described for examples 8c and9a; step 1) with propionyl chloride.

[0322] Example 10d was prepared by acylation of7-(2,4,6-trimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine(prepared from example 8b using procedures described for examples 8c and9a; step 1) with methoxyacetyl chloride.

Example 112-[2-Methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylmethyl]-1,2,3,4-tetrahydroisoguinolineDihydrochloride

[0323]

[0324] A solution of 140 mg of(3,4-dihydro-1H-isoquinolin-2-yl)[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]methanonein 6 mL of dry tetrahydrofuran was treated with 4 mL of 1 Mborane-tetrahydrofuran complex in tetrahydrofuran and stirred under anatmosphere of nitrogen at room temperature for 15 h. The mixture wasslowly treated with 5 mL of concentrated HCl and heated at 45° C. for 5h. The mixture was then cooled to room temperature and made alkaline bythe cautious addition of solid sodium bicarbonate. After diluting withwater, the mixture was washed twice with 30 mL portions of ethylacetate. The combined organic extracts were washed with 30 mL of brine,dried over magnesium sulfate, and evaporated to dryness. The residue waspurified on a flash silica gel column eluting with 10% acetone/hexanesolvent yielding 47 mg of the free base. The dihydrochloride salt wasprepared using 1 M HCl in ether giving 49 mg of2-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylmethyl]-1,2,3,4-tetrahydroisoquinolinedihydrochloride, mp 236.4-241° C. TABLE 6 Compounds prepared in Examples10a-10d, and 11. MH+ mp observed Example Structure Name (° C.)(predicted) 10a

7-(2-Chloro-4,6-dimethylphenyl)- 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3- carboxylic acid cyclopropylmethylpropylamide120.6-122.0 415 (415) 10b

(3,4-Dihydro-1H-isoquinolin-2-yl)- [2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H- pyrazolo[3,4-b]pyridin-3-yl]- methanone80.3-87.7 415 (415) 10c

N-[2-Methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridin-3-yl]propionamide 226-228327 (327) 10d

2-Methoxy-N-[2-methyl-7-(2,4,6- trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]acetamide 133.8-135.0 343 (343) 11

2-[2-Methyl-7-(2,4,6-trimethyl- phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylmethyl]- 1,2,3,4-tetrahydroisoquinolinedihydrochloride 236.4-241.0 401 (401)

Example 12a7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine

[0325]

[0326] A mixture of 200 mg of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one(Example 1, step 5) and 337 mg of triphenylphosphine in 15 mL of drytetrahydrofuran was treated with 124 mg of 4-heptanol and 224 mg ofdiethylazodicarboxylate. The mixture was placed under an atmosphere ofnitrogen and stirred at room temperature for 16 h. The solvent wasevaporated and the residue was purified by flash column chromatographyon silica gel using 15% ethyl acetate/hexane as solvent giving 84 mg of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridineas a colorless oil, ms m/z 390 (MH⁺).

Example 12b7-(2,4-Dichlorophenyl)-2-methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridineHydrochloride

[0327] Example 12b was prepared according to the procedure described inExample 12a, except that7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-onewas replaced by7-(2,4-dichlorophenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one.

Example 12c7-(2-methyl-4-methoxyphenyl)-2-methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridinehydrochloride

[0328] Example 12c was prepared according to the procedure described inExample 12a, except that7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-onewas replaced by7-(4-methoxy-2-methyl-phenyl)-2-methyl-1,2,4,5,6,7-hexahydro-pyrazolo[3,4-b]pyridin-3-one.

Example 12dDimethyl-{4-methyl-5-[2-methyl-3-(1-propylbutoxy)-2,4,5,6-tetrahydro-pyrazolo[3,4-b]pyridin-7-yl]-pyridin-2-yl}-amine

[0329] Example 12c was prepared according to the procedure described inExample 12a, except that7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-onewas replaced by7-(6-dimethylamino-4-methylpyridin-3-yl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one.TABLE 7 Compounds prepared in Examples 12a-12d. MH+ mp observed ExampleStructure Name (° C.) (predicted) 12a

7-(2-Chloro-4,6-dimethylphenyl)-2- methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H- pyrazolo[3,4-b]pyridine oil 390 (390) 12b

7-(2,4-Dichlorophenyl)-2-methyl-3- (1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine hydrochloride oil 396 (396) 12c

7-(4-Methoxy-2-methylphenyl)-2- methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridine oil 372 (372) 12d

Dimethyl-{4-methyl-5-[2-methyl-3- (1-propylbutoxy)-2,4,5,6-tetrahydro-pyrazolo[3,4-b]pyridin-7-yl]-pyridin- 2-yl}-amine oil 386 (386)

Example 13a

[0330]2-Methyl-3-(2-trifluoromethylphenyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine

[0331] A mixture of 200 mg of3-bromo-2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine,124 mg of 2-trifluoromethylphenylboronic acid, and 14 mg oftetrakistriphenylphosphine palladium (0) in 2 mL of dioxane was treatedwith a solution of 210 mg of sodium carbonate in 2 mL of water. Themixture was placed under an atmosphere of argon and heated to 100° C.for 20 h. The mixture was cooled to room temperature, diluted with 20 mLof ethyl acetate, washed with 20 mL of 1 M HCl and 20 mL of brine, driedover magnesium sulfate, and evaporated to dryness. The residue waspurified by flash silica gel column chromatography using 7%acetone/hexane as solvent yielding 87 mg of2-methyl-3-(2-trifluoromethylphenyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine,mp 59-63° C.

Example 13b3-(2,6-Dimethoxyphenyl)-2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine

[0332] Example 13b was prepared according to the procedure described inExample 13a, except that 2-trifluoromethylphenylboronic acid wasreplaced by 2,6-bismethoxyphenylboronic acid. TABLE 8 Compounds preparedin Examples 13a-13b. MH+ mp observed Example Structure Name (° C.)(predicted) 13a

2-Methyl-3-(2- trifluoromethylphenyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7- tetrahydro-2H-pyrazolo[3,4- b]pyridine 59-63400 (400) 13b

3-(2,6-Dimethoxyphenyl)-2- methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H- pyrazolo[3,4-b]pyridine 169.9-172.8 392 (392)

Example 14 Contemplated Compounds

[0333] In addition to the compounds exemplified herein, the compoundsshown in Table 9 are contemplated to fall within the scope of theinvention. In addition, the compounds shown in Table 9 illustratecertain species of compounds that are generically described herein.TABLE 9 Contemplated compounds

Example 15 Composition for Oral Administration

[0334] Ingredient % wt./wt. Active ingredient 20.0% Lactose 79.5%Magnesium stearate 0.5%

[0335] The ingredients are mixed and dispensed into capsules containingabout 100 mg each; one capsule would approximate a total daily dosage.

Composition for Oral Administration

[0336] Ingredient % wt./wt. Active ingredient 20.0% Magnesium stearate0.5% Crosscarmellose sodium 2.0% Lactose 76.5% PVP(polyvinylpyrrolidine) 1.0%

[0337] The ingredients are combined and granulated using a solvent suchas methanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine.

Composition for Oral Administration

[0338] Ingredient Amount Active compound 1.0 g Fumaric acid 0.5 g Sodiumchloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 g Granulatedsugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.)1.0 g Flavoring 0.035 ml Colorings 0.5 mg Distilled water q.s. to 100 ml

[0339] The ingredients are mixed to form a suspension for oraladministration.

Parenteral Formulation (IV)

[0340] Ingredient % wt./wt. Active ingredient 0.25 g  Sodium Chloride qsto make isotonic Water for injection to  100 ml

[0341] The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

Suppository Formulation

[0342] Ingredient % wt./wt. Active ingredient 1.0% Polyethylene glycol1000 74.5% Polyethylene glycol 4000 24.5%

[0343] The ingredients are melted together and mixed on a steam bath,and poured into molds containing 2.5 g total weight.

Topical Formulation

[0344] Ingredients grams Active compound 0.2-2 Span 60 2 Tween 60 2Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA(butylated hydroxy anisole) 0.01 Water q.s. 100

[0345] All of the ingredients, except water, are combined and heated toabout 60° C. with stirring. A sufficient quantity of water at about 60°C. is then added with vigorous stirring to emulsify the ingredients, andwater then added q.s. about 100 g.

Nasal Spray Formulations

[0346] Several aqueous suspensions containing from about 0.025-0.5percent active compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50-100 microliters of formulation peractuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 16 Intracellular cAMP Stimulation Assay

[0347] Human Y-79 retinoblastoma cells are grown in RPMI 1640 mediumwith 15% FBS. Measures of cAMP accumulation are performed by using NENAdenylyl Cyclase FlashPlate kit (SMP004). The cells are separated fromculture medium, washed twice with PBS (150×g, 8 min), resuspended (2E+6cells/ml) in Stimulation Buffer (provided in the kit), and then added to96-well FlashPlates, (50,000 cells per well). Various concentrations oftest compounds are incubated with the cells for 20 min prior to theaddition of hCRF (30 nM). The total assay volume is 100 μl. The assay isterminated after 20 min after addition of the hCRF by addition ofDetection Buffer and [¹²⁵I]cAMP. After 2 hr at room temperature themixtures are aspirated and the bound radioactivity is measured with aPackard TopCount. The potency (IC₅₀ values) of test compounds ininhibiting the hCRF-stimulated accumulation of cAMP is determined bynonlinear regression analyses with interactive curve-fitting procedures.

EXAMPLE 17 CRF Receptor Binding Assay

[0348] Human IMR-32 neuroblastoma cells are grown to 80% confluence inMEM medium containing 10% heat-inactivated FBS, 1 mM Sodium Pyruvate,and 0.1 mM nonessential amino acids. Celll membranes are preparedaccording the method of Dieterich and DeSouza (1996). The cells (˜5E+9)are resuspended in 10 volumes of wash buffer (5 mM Tris HCl, 10 mMMgCl₂, 2 mM EGTA, pH 7.4 at RT), homogenized with a Polytron, and thencentrifuged at 45,000 G for 20 min at 4° C. The membrane pellets arewashed twice with wash buffer (45,000 G for 20 min at 4° C.) and thenresuspended (50 mM Tris HCl, 10 mM MgCl₂, 2 mM EGTA, pH 7.4 at RT).Protein concentration is determined using Pierce reagents and BSA asstandard. Aliquots of 1-1.5 ml are stored at −80° C. until bindingassay.

[0349] The competition binding assay is performed in a final volume of250 μl, which contains assay buffer (50 mM Tris-HCl, 10 mM MgCl₂, 2 mMEGTA, 0.2% BSA, 0.1 mM bacitracin and 100 kIU/ml aprotinin pH 7.2 atR.T.), 0.05 nM [¹²⁵I]Tyr⁰-ovine CRF (Du Pont New England Nuclear), 50 μgof membrane protein, and test compound at various concentrations.Non-specific binding is determined with 1 uM hCRF. Binding reactions areterminated after 2 hr incubation at 25° C. by filtering through 96-wGF/C filter plate using a Packard Harvester (Filtermate 196). The 96-wfilter plate is pre-treated with 0.3% polyethyleneimine and pre-washedwith washing buffer (50 mM Tris-HCl, 10 mM MgCl₂, 2 mM EGTA, 0.2% BSA,pH 7.2 at 4° C.). Unbound radioactivity is removed by four rapid washes(0.8 ml/well) with wash buffer. The radioactivity is quantified using aPackard TopCount. Data are analyzed using non-linear iterative curvefitting to obtain IC50 and Hill slope values. PKi values are derivedfrom pIC₅₀ values (−log of IC₅₀).

[0350] The compounds of the present invention were active in thereceptor binding and functional assay. The IC₅₀ of of representativeexamples in the CRF functional assay are shown in Table 10. TABLE 10CRF1 receptor binding affinity of compounds of Formula I. Example hCRF1(pIC₅₀)  1  5.97  5c 4.95  6e 6.63  7b 7.06  9c 6.08 11  4.92 12b 7.5613a 6.11

[0351] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, orprocess step or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A compound of Formula I or Formula II:

wherein: R¹ is —OR^(a), —NR^(a)R^(b), —CR^(c)R^(d)R^(e), CO₂R^(a), or—C(O)NR^(a)R^(b); or R¹ is hydrogen, halogen, cycloalkenyl, aryl, orheteroaryl, where each aryl or heteroaryl is optionally substituted withone or more substituents independently selected from C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, halogen, haloalkyl, cyano,nitro, —C(O)NR^(a′)R^(b′), and —NR^(a′)R^(b′), where R^(a′) and R^(b′)are each independently selected from the group consisting of hydrogen,C₁₋₉alkyl, and C₁₋₉alkylcarbonyl; R² is hydrogen, C₁₋₆alkyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl, C₁₋₆alkylcarbonyl,C₁₋₆alkylsulfonyl, aryl, or arylalkyl, wherein said aryl or arylalkyl isoptionally substituted with one or more substituents independentlyselected from C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen; R³ and R⁴are each independently selected from hydrogen and C₁₋₆alkyl, or R³ andR⁴ are taken together with the carbon to which they are attached to forma C₃₋₆cycloalkyl ring; Ar is aryl or heteroaryl, each optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl,dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and—NR^(a″)R^(b″), where R^(a″) and R^(b″) are each independently selectedfrom the group consisting of hydrogen, C₁₋₉alkyl, and C₁₋₉alkylcarbonyl;R^(a) and R^(b) are each independently selected from the groupconsisting of hydrogen, C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,C₁₋₆alkylthioalkyl, carboxyalkyl, C₁₋₆-alkoxycarbonyl,C₁₋₆-alkoxyC₁₋₃-alkylcarbonyl, acyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylalkyl, di-C₃₋₆cycloalkylC₁₋₃alkyl, C₁₋₆heteroalkyl,aminoalkyl, aminocarbonylalkyl, cyanoalkyl, C₅₋₈heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,phenylalkyl, diphenylalkyl, phenylsulfonyl optionally substituted asdescribed for phenyl below, and C₁₋₃alkyl substituted with both aC₃₋₆cycloalkyl and a phenyl group, wherein each of said cycloalkyl,phenyl, aryl, or heteroaryl groups is optionally substituted with one ormore substituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, andhalogen, and each of said amino groups is optionally monosubstituted ordisubstituted with alkyl; or R^(a) and R^(b) are taken together with thenitrogen to which they are attached form an heterocyclyl or heteroarylring selected from the group consisting of pyrrolidine, piperidine,homopiperidine, tetrahydropyridine, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine,hexahydropyrimidine, pyrazolidine, piperazine, morpholine, imidazoline,pyrrole, pyrazole, and imidazole, where each of said rings is optionallysubstituted with one or more substituents selected from the groupconsisting of hydroxy, oxo, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl,aminoalkyl, acyl, acylamino, aminocarbonyl, aminocarbonylalkyl,aminocarbonylamino, aminosulfonyl, alkylsulfonylamino,aminosulfonylamino, and phenyl, wherein each of said phenyl groups isoptionally substituted with one or more groups independently selectedfrom C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,and halogen, and each of said amino groups is optionally monosubstitutedor disubstituted with alkyl, or is contained in a pyrrolidinyl,piperidinyl, morpholinyl, or piperazinyl group; R^(c) is hydrogen,hydroxy, C₁₋₆alkoxy, or —NR^(a′″)R^(b′″); R^(d) and R^(e) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,hydroxyalkyl, C₁₋₆alkoxyalkyl, C₁₋₆alkylthioalkyl, heteroalkyl,heterocyclyl, heterocyclylalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl,di-C₃₋₆cycloalkyl-C₁₋₃alkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, phenylalkyl, diphenyl-C₁₋₃alkyl, and C₁₋₃alkylsubstituted with both a C₃₋₆cycloalkyl and a phenyl group, wherein eachof said cycloalkyl, phenyl, aryl, or heteroaryl groups is optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino,alkylamino, dialkylamino, and halogen; or R^(c) and R^(d) are takentogether to form a divalent group selected from C₁₋₆alkylidenyl,C₁₋₆heteroalkylidenyl, C₃₋₆cycloalkylidenyl, C₃₋₆cycloalkyl-alkylidenyl,C₃₋₆cycloalkylalkyl-alkylidenyl, C₃₋₆heterocyclylidenyl,C₃₋₆heterocyclyl-C₁₋₃alkylidenyl, C₃₋₆heterocyclylalkyl-C₁₋₃alkylidenyl,aryl-C₁₋₃alkylidenyl, aryl-C₁₋₃alkyl-alkylidenyl,heteroaryl-C₁₋₃alkylidenyl, and heteroarylalkyl-C₁₋₃alkylidenyl, whereineach of said cycloalkyl, aryl, or heteroaryl groups is optionallysubstituted with one or more substituents independently selected fromC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino, andhalogen; or R^(d) and R^(e) are taken together with the carbon to whichthey are attached to form a cycloalkyl or heterocyclyl ring; R^(a′″) andR^(b′″) are each independently selected from the group consisting ofhydrogen, C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl, C₁₋₆alkylthioalkyl,carboxyalkyl, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkoxyC₁₋₃-alkylcarbonyl, acyl,C₃₋₆cycloalkyl, C₃-₆cycloalkylalkyl, di-C₃₋₆cycloalkyl-C₁₋₃alkyl,C₁₋₆heteroalkyl, aminoalkyl, aminocarbonylalkyl, cyanoalkyl,C₅₋₈heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, phenylalkyl, diphenyl-C₁₋₃alkyl, and C₁₋₃alkylsubstituted with both a C₃₋₆cycloalkyl and a phenyl group, wherein eachof said cycloalkyl, phenyl, aryl, or heteroaryl groups is optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino,alkylamino, dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl,alkylsulfonyloxy, and halogen, and each of said amino groups isoptionally monosubstituted or disubstituted with alkyl; or, R^(a′″) andR^(b″) are taken together with the nitrogen to which they are attachedform an heterocyclyl or heteroaryl ring selected from the groupconsisting of pyrrolidine, piperidine, homopiperidine,tetrahydropyridine, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine,hexahydropyrimidine, pyrazolidine, piperazine, morpholine, imidazoline,pyrrole, pyrazole, and imidazole, where each of said rings is optionallysubstituted with one or more substituents selected from the groupconsisting of hydroxy, oxo, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl,aminoalkyl, acyl, acylamino, aminocarbonyl, aminocarbonylalkyl,aminocarbonylamino, aminosulfonyl, alkylsulfonylamino,aminosulfonylamino, and phenyl, wherein each of said phenyl groups isoptionally substituted with one or more groups independently selectedfrom C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,and halogen, and each of said amino groups is optionally monosubstitutedor disubstituted with alkyl, or is contained in a pyrrolidinyl,piperidinyl, morpholinyl, or piperazinyl group; n is an integer selectedfrom 0, 1 and 2; a is a single or double bond; providing that (i) when nis 0, R¹ is not hydrogen; (ii) when n is 0 and a is a double bond, R⁴ isabsent; and (iii) when n is 1 or 2, a is a single bond; or individualisomers, racemic or non-racemic mixtures of isomers, or pharmaceuticallyacceptable salts thereof.
 2. The compound of claim 1, wherein thecompound is of Formula I:

and R¹ is —OR^(a), —NR^(a)R^(b), —CR^(c)R^(d)R^(e), CO₂R^(a), or—C(O)NR^(a)R^(b); or R¹ is halogen, cycloalkenyl, aryl, or heteroaryl,where each aryl or heteroaryl is optionally substituted with one or moresubstituents independently selected from C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, halogen, haloalkyl, cyano, nitro,—C(O)NR^(a′)R^(b′), and —NR^(a′)R^(b′), where R^(a′) and R^(b′) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉ alkylcarbonyl.
 3. The compound of claim 2, wherein the integern is 1 or 2, and a is a single bond.
 4. The compound of claim 3, whereinAr is a di- or tri-substituted phenyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl.
 5. The compound of claim 4, wherein R³ and R⁴ areeach independently selected from hydrogen and methyl.
 6. The compound ofclaim 3, wherein Ar is a 2,4-disubstituted or 2,4,6-trisubstitutedphenyl.
 7. The compound of claim 3, wherein Ar is a 2,4-disubstituted or2,4,6-trisubstituted phenyl, and the substituents are each independentlyselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkylthio, halogen, haloalkyl, cyano, alkylamino, dialkylamino, andnitro.
 8. The compound of claim 7, wherein R² is hydrogen, C₁₋₆alkyl, orC₁₋₆alkylcarbonyl.
 9. The compound of claim 8, wherein R³ and R⁴ areeach independently selected from hydrogen and methyl; and the integer nis
 1. 10. The compound of claim 5, wherein R¹ is —CR^(c)R^(d)R^(e) andR^(c) is hydroxy.
 11. The compound of claim 10, wherein R^(d) and R^(e)are each independently selected from the group consisting of hydrogen,C₁₋₉alkyl, C₁₋₆alkoxyalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl, where each of said aryl orheteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen.
 12. The compound of claim10, wherein R^(d) and R^(e) are each independently selected from thegroup consisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl, aryl, and heteroaryl,where each of said aryl or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen.
 13. Thecompound of claim 12, wherein R² is C₁₋₆alkyl; R³ and R⁴ are hydrogen;and Ar is a 2,4-disubstituted or 2,4,6-trisubstituted phenyl, and thesubstituents are each independently selected from the group consistingof C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl, cyano, and —NR^(a″)R^(b″),where R^(e) and R^(b) are each independently selected from the groupconsisting of hydrogen and C₁₋₉alkyl.
 14. The compound of claim 10,wherein R^(d) and R^(e) are taken together to form a cycloalkyl orheterocyclyl group.
 15. The compound of claim 5, wherein R¹ is—CR^(c)R^(d)R^(e); R^(e) is selected from the group consisting ofC₁₋₉alkyl, C₁₋₆alkoxyalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl, where each of said aryl orheteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen; and R^(c) and R^(d) aretaken together to form a divalent group selected from C₁₋₆alkylidenyl,C₁₋₆heteroalkylidenyl, C₃₋₆cycloalkylidenyl, C₃₋₆cycloalkyl-alkylidenyl,C₃₋₆cycloalkylalkyl-alkylidenyl, C₃₋₆heterocyclylidenyl,C₃₋₆heterocyclyl-C₁₋₃alkylidenyl, C₃₋₆heterocyclylalkyl-C₁₋₃alkylidenyl,aryl-C₁₋₃alkylidenyl, aryl-C₁₋₃alkyl-alkylidenyl,heteroaryl-C₁₋₃alkylidenyl, and heteroarylalkyl-C₁₋₃alkylidenyl, whereineach of said cycloalkyl, aryl, or heteroaryl groups is optionallysubstituted with one or more substituents independently selected fromC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino, andhalogen.
 16. The compound of claim 15, wherein R^(c) and R^(d) are takentogether to form a divalent group selected from C₁₋₆alkylidenyl,C₃₋₆cycloalkyl-alkylidenyl, aryl-C₁₋₃alkylidenyl, andheteroaryl-C₁₋₃alkylidenyl.
 17. The compound of claim 5, wherein R¹ is—CR^(c)R^(d)R^(e); R^(e) is selected from the group consisting ofC₁₋₉alkyl, C₁₋₆alkoxyalkyl, and heteroaryl, where the heteroaryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy,and halogen; and R^(c) and R^(d) are taken together to form a divalentgroup selected from C₁₋₆alkylidenyl, C₃₋₆cycloalkyl-alkylidenyl,C₃₋₆heterocyclyl-C₁₋₃alkylidenyl, aryl-C₁₋₃alkylidenyl, andheteroaryl-C₁₋₃alkylidenyl, wherein each of said aryl, or heteroarylgroups is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, amino, alkylamino,and dialkylamino.
 18. The compound of claim 5, wherein R¹ is—CR^(c)R^(d)R^(e) and R^(c) is hydrogen.
 19. The compound of claim 18,wherein R^(d) and R^(e) are each independently selected from the groupconsisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl,where each of said aryl or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen.
 20. Thecompound of claim 18, wherein R^(d) and R^(e) are each independentlyselected from the group consisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl, aryl,and heteroaryl, where each of said aryl or heteroaryl groups isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy,and halogen; R² is C₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar is a2,4-disubstituted or 2,4,6-trisubstituted phenyl, and the substituentsare independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, halogen, haloalkyl, cyano, and —NR^(a″)R^(b″), where R^(a″)and R^(b″) are each independently selected from the group consisting ofhydrogen and C₁l₉alkyl.
 21. The compound of claim 5, wherein R¹ is—NR^(a)R^(b); —C(O)NR^(a)R^(b); or CR^(c)R^(d)R^(e), where R^(c) isNR^(a′″)R^(b′″); and, R^(d) and R^(e) are each independently selectedfrom the group consisting of hydrogen and C₁₋₉alkyl.
 22. The compound ofclaim 21, wherein R^(a), R^(b), R^(a′″), and R^(b′″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,hydroxyalkyl, C₁₋₆alkoxyalkyl, C₃₋₆cycloalkylalkyl, heterocyclylalkyl,arylalkyl, and heteroarylalkyl, wherein each of said aryl or heteroarylgroups is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆alkyl,haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl,cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, and halogen, and eachof said amino groups is optionally monosubstituted or disubstituted withalkyl.
 23. The compound of claim 21, wherein R^(a) and R^(b), or R^(a′″)and R^(b′″), are taken together with the nitrogen to which they areattached form an heterocyclyl ring selected from the group consisting ofpyrrolidine, piperidine, homopiperidine, tetrahydropyridine,1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline,tetrahydropyrimidine, hexahydropyrimidine, pyrazolidine, piperazine,morpholine, and imidazoline, where each of said rings is optionallysubstituted with one or more substituents independently selected fromthe group consisting of hydroxy, oxo, alkyl, aminoalkyl, acyl,acylamino, aminocarbonyl, aminocarbonylalkyl, and aminocarbonylamino,and each of said amino groups is optionally monosubstituted ordisubstituted with alkyl, or is contained in a pyrrolidinyl,piperidinyl, morpholinyl, or piperazinyl group.
 24. The compound ofclaim 5, wherein R¹ is —NR^(a)R^(b); R^(a) is selected from the groupconsisting of hydrogen, C₁₋₉alkyl, and C₁₋₆alkoxyalkyl; and R^(b) isselected from the group consisting of C₁₋₉alkyl, hydroxyalkyl,C₁₋₆alkoxyalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl,wherein each of said aryl or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino,dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl,alkylsulfonyloxy, and halogen, and each of said amino groups isoptionally monosubstituted or disubstituted with alkyl.
 25. The compoundof claim 24, wherein R² is C₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar isa 2,4-disubstituted or 2,4,6-trisubstituted phenyl, and the substituentsare independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, halogen, haloalkyl, cyano, and —NR^(a″)R^(b″), where R^(a″)and R^(b″) are each independently selected from the group consisting ofhydrogen and C₁₋₉alkyl.
 26. The compound of claim 5, wherein R¹ is—CR^(c)R^(d)R^(e); R^(c) is —NR^(a′″)R^(b′″); R^(d) and R^(e) are eachindependently selected from the group consisting of hydrogen andC₁₋₉alkyl; R^(a′″) is selected from the group consisting of hydrogen,C₁₋₉alkyl, and C₁₋₆alkoxyalkyl; and R^(b′″) is selected from the groupconsisting of C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,heterocyclylalkyl, arylalkyl, and heteroarylalkyl, wherein each of saidaryl or heteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, andhalogen, and each of said amino groups is optionally monosubstituted ordisubstituted with alkyl.
 27. The compound of claim 26, wherein R² isC₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar is a 2,4-disubstituted or2,4,6-trisubstituted phenyl, and the substituents are independentlyselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen,haloalkyl, cyano, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen andC₁₋₉alkyl.
 28. The compound of claim 5, wherein R¹ is —OR^(a), and R^(a)is as defined in claim
 1. 29. The compound of claim 28, wherein R^(a) isselected from the group consisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl,C₃₋₆cycloalkylalkyl, arylalkyl, and heteroarylalkyl, wherein each ofsaid cycloalkyl, aryl, or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino,dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl,alkylsulfonyloxy, and halogen, and each of said amino groups isoptionally monosubstituted or disubstituted with alkyl.
 30. The compoundof claim 29, wherein R² is C₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar isa 2,4-disubstituted or 2,4,6-trisubstituted phenyl, and the substituentsare independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, halogen, haloalkyl, cyano, and —NR^(a″)R^(b″), where R^(a″)and R^(b″) are each independently selected from the group consisting ofhydrogen and C₁₋₉alkyl.
 31. The compound of claim 5, wherein R¹ is arylor heteroaryl, where said aryl or heteroaryl is optionally substitutedwith one or more substituents independently selected from C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a′)R^(b′), where R^(a′) and R^(b′) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁-alkylcarbonyl.
 32. The compound of claim 31, where said aryl orheteroaryl is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl,cyano, and —NR^(a″)R^(b″), where R^(a′) and R^(b′) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl.
 33. The compound of claim 3, wherein Ar is a di-or tri-substituted pyridinyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl.
 34. The compound of claim 33, wherein R³ and Rare each independently selected from hydrogen and methyl.
 35. Thecompound of claim 3, wherein Ar is a 2,4-disubstituted,2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and thesubstituents are each independently selected from the group consistingof C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl,aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen,haloalkyl, cyano, nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) areeach independently selected from the group consisting of hydrogen,C₁₋₉alkyl, and C₁₋₉alkylcarbonyl.
 36. The compound of claim 3, whereinAr is a 2,4-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstitutedpyridin-3-yl, and the substituents are each independently selected fromthe group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl,alkylamino, and dialkylamino.
 37. The compound of claim 36, wherein R²is hydrogen, C₁₋₆alkyl, or C₁₋₆alkylcarbonyl.
 38. The compound of claim37, wherein R³ and R⁴ are each independently selected from hydrogen andmethyl; and the integer n is
 1. 39. The compound of claim 34, wherein R¹is —CR_(c)R^(d)R^(e) and R^(c) is hydroxy.
 40. The compound of claim 39,wherein R^(d) and R^(e) are each independently selected from the groupconsisting of hydrogen, C₁₋₉alkyl, C₁₋₆alkoxyalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl,where each of said aryl or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen.
 41. Thecompound of claim 39, wherein R^(d) and R^(e) are each independentlyselected from the group consisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl, aryl,and heteroaryl, where each of said aryl or heteroaryl groups isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy,and halogen.
 42. The compound of claim 41, wherein R² is C₁₋₆alkyl; R³and R⁴ are hydrogen; and Ar is a 2,4-disubstituted, 2,6-disubstituted,or 2,4,6-trisubstituted pyridin-3-yl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, halogen, haloalkyl, and —NR^(a″)R^(b″), where R^(a″) andR^(b″) are each independently selected from the group consisting ofhydrogen and C₁₋₉alkyl.
 43. The compound of claim 39, wherein R^(d) andR^(e) are taken together to form a cycloalkyl or heterocyclyl group. 44.The compound of claim 34, wherein R¹ is —CR^(c)R^(d)R^(e); R^(e) isselected from the group consisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl, where each of said aryl or heteroaryl groups isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy,and halogen; and R^(c) and R^(d) are taken together to form a divalentgroup selected from C₁₋₆alkylidenyl, C₁₋₆heteroalkylidenyl,C₃₋₆cycloalkylidenyl, C₃₋₆cycloalkyl-alkylidenyl,C₃₋₆cycloalkylalkyl-alkylidenyl, C₃₋₆heterocyclylidenyl,C₃₋₆heterocyclyl-C₁₋₃alkylidenyl, C₃₋₆heterocyclylalkyl-C₁₋₃alkylidenyl,aryl-C₁₋₃alkylidenyl, aryl-C₁₋₃alkyl-alkylidenyl,heteroaryl-C₁₋₃alkylidenyl, and heteroarylalkyl-C₁₋₃alkylidenyl, whereineach of said cycloalkyl, aryl, or heteroaryl groups is optionallysubstituted with one or more substituents independently selected fromC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino, andhalogen.
 45. The compound of claim 44, wherein R^(c) and R^(d) are takentogether to form a divalent group selected from C₁₋₆alkylidenyl,C₃₋₆cycloalkyl-alkylidenyl, aryl-C₁₋₃alkylidenyl, andheteroaryl-C₁₋₃alkylidenyl, wherein each of said aryl or heteroarylgroups is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino,alkylamino, dialkylamino, and halogen.
 46. The compound of claim 34,wherein R¹ is —CR^(c)R^(d)R^(e); R^(e) is selected from the groupconsisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl, and heteroaryl, where theheteroaryl is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆alkyl,haloalkyl, C₁₋₆alkoxy, and halogen; and R^(c) and R^(d) are takentogether to form a divalent group selected from C₁₋₆alkylidenyl,C₃₋₆cycloalkyl-alkylidenyl, C₃₋₆heterocyclyl-C₁₋₃alkylidenyl,aryl-C₁₋₃alkylidenyl, and heteroaryl-C₁₋₃alkylidenyl, wherein each ofsaid aryl, or heteroaryl groups is optionally substituted with one ormore substituents independently selected from C₁₋₆alkyl, C₁₋₆alkoxy,amino, alkylamino, and dialkylamino.
 47. The compound of claim 34,wherein R¹ is —CR_(c)R_(d) ^(R) ^(e) and R^(c) is hydrogen.
 48. Thecompound of claim 47, wherein R^(d) and R^(e) are each independentlyselected from the group consisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl, where each of said aryl or heteroaryl groups isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy,and halogen.
 49. The compound of claim 47, wherein R^(d) and R^(e) areeach independently selected from the group consisting of C₁₋₉alkyl,C₁₋₆alkoxyalkyl, optionally substituted aryl, and optionally substitutedheteroaryl,; R² is C₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar is a2,4-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstitutedpyridin-3-yl, and the substituents are independently selected from thegroup consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl, and—NR^(a″)R^(b″), where R^(a″) and R^(b″) are each independently selectedfrom the group consisting of hydrogen and C₁₋₉alkyl.
 50. The compound ofclaim 34, wherein R¹ is —NR^(a)R^(b); —C(O)NR^(a)R^(b); orCR^(c)R^(d)R^(e) where R^(c) is NR^(a′″)R^(b′″) and R^(d) and R^(e) areeach independently selected from the group consisting of hydrogen andC₁₋₉alkyl.
 51. The compound of claim 50, wherein R^(a), R^(b), R^(a′″),and R^(b′″) are each independently selected from the group consisting ofhydrogen, C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl, C₃₋₆cycloalkylalkyl,heterocyclylalkyl, optionally substituted arylalkyl, and optionallysubstituted heteroarylalkyl.
 52. The compound of claim 50, wherein R^(a)and R^(b), or R^(a′″)and R^(b′″), are taken together with the nitrogento which they are attached form an heterocyclyl ring selected from thegroup consisting of pyrrolidine, piperidine, homopiperidine,tetrahydropyridine, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine,hexahydropyrimidine, pyrazolidine, piperazine, morpholine, andimidazoline, where each of said rings is optionally substituted with oneor more substituents independently selected from the group consisting ofhydroxy, oxo, alkyl, aminoalkyl, acyl, acylamino, aminocarbonyl,aminocarbonylalkyl, and aminocarbonylamino, and each of said aminogroups is optionally monosubstituted or disubstituted with alkyl, or iscontained in a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinylgroup.
 53. The compound of claim 34, wherein R¹ is —NR^(a)R^(b); R^(a)is selected from the group consisting of hydrogen, C₁₋₉alkyl, andC₁₋₆alkoxyalkyl; and R^(b) is selected from the group consisting ofC₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl, heterocyclylalkyl, optionallysubstituted arylalkyl, and optionally substituted heteroarylalkyl. 54.The compound of claim 53, wherein R² is C₁₋₆alkyl; R³ and R⁴ arehydrogen; and Ar is a 2,4-disubstituted, 2,6-disubstituted, or2,4,6-trisubstituted pyridin-3-yl, and the substituents areindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, halogen, haloalkyl, and —NR^(a″)R^(b″), where R^(a″) andR^(b″) are each independently selected from the group consisting ofhydrogen and C₁₋₉alkyl.
 55. The compound of claim 34, wherein R¹ is—CR^(c)R^(d)R^(e); R^(c) is —NR^(a′″)R^(b′″); R^(d) and R^(e) are eachindependently selected from the group consisting of hydrogen andC₁₋₉alkyl; R^(a′″) is selected from the group consisting of hydrogen,C₁₋₉alkyl, and C₁₋₆alkoxyalkyl; and R^(b′″) is selected from the groupconsisting of C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,heterocyclylalkyl, optionally substituted arylalkyl, and optionallysubstituted heteroarylalkyl.
 56. The compound of claim 55, wherein R² isC₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar is a 2,4-disubstituted,2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and thesubstituents are independently selected from the group consisting ofC₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl, and —NR^(a″)R^(b″), whereR^(a″) and R^(b″) are each independently selected from the groupconsisting of hydrogen and C₁₋₉alkyl.
 57. The compound of claim 34,wherein R¹ is —OR^(a).
 58. The compound of claim 57, wherein R^(a) isselected from the group consisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl,optionally substituted C₃₋₆cycloalkylalkyl, optioally substitutedarylalkyl, and optionally substitutd heteroarylalkyl.
 59. The compoundof claim 58, wherein R² is C₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar isa 2,4-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstitutedpyridin-3-yl, and the substituents are independently selected from thegroup consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl, and—NR^(a″)R^(b″), where R^(a″) and R^(b″) are each independently selectedfrom the group consisting of hydrogen and C₁₋₉alkyl.
 60. The compound ofclaim 34, wherein R¹ is aryl or heteroaryl, where said aryl orheteroaryl is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, halogen, haloalkyl, cyano, nitro, and —NR^(a′)R^(b′),where R^(a′) and R^(b′) are each independently selected from the groupconsisting of hydrogen, C₁₋₉alkyl, and C₁₋₉alkylcarbonyl.
 61. Thecompound of claim 60, where said aryl or heteroaryl is optionallysubstituted with one or more substituents independently selected fromC₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl, cyano, and —NR^(a′)R^(b′),where R^(a′) and R^(b′) are each independently selected from the groupconsisting of hydrogen, C₁₋₉alkyl, and C₁₋₉alkylcarbonyl.
 62. Apharmaceutical composition comprising a therapeutically effective amountof at least one compound of claim 1 in admixture with at least onepharmaceutically acceptable carrier.
 63. A method for treating a subjecthaving a disease state that is alleviated by treatment with a CRFreceptor antagonist, which comprises administering to such a subject atherapeutically effective amount of a compound of claim
 1. 64. Themethod of claim 63, wherein the disease state is selected from the groupconsisting of phobias, stress-related illnesses, mood disorders, eatingdisorders, generalized anxiety disorders, stress-inducedgastrointestinal dysfunctions, neurodegenerative diseases, andneuropsychiatric disorders.
 65. A process for preparing a compound ofclaim 1, where the compound is of Formula I, and a is a single bond,comprising: (a) treating a compound of formula:

where R³, R⁴, and Ar are as defined in claim 1, with a compound offormula:

where R is alkyl, to form a first intermediate of formula:

(b) treating the first intermediate with a compound of formula:R²—NHNH₂, where R² is as defined in claim 1, to form a secondintermediate of formula:


66. The process of claim 65, further comprising (c) treating the secondintermediate with a compound of formula: R^(a)—OH, where R^(a) is asdefined in claim 1, to form a compound of Formula I, wherein R¹ is—OR^(a).
 67. The process of claim 65, further comprising (c) treatingthe second intermediate with a brominating reagent to form a thirdintermediate of formula:


68. The process of claim 67, further comprising (d) converting the thirdintermediate into an anion of formula:

(e) treating the anion with a compound of formula:

where R^(d) and R^(e) are as defined in claim 1, to form a compound ofFormula I, wherein R¹ is —CR_(c)R_(d)R_(e), and R^(c) is hydroxy. 69.The process of claim 68, further comprising (e) treating the anion witha compound of formula: C(O)₂, to form a compound of Formula I, whereinR¹ is —CO₂R^(a).
 70. The process of claim 67, further comprising (d)treating the third intermediate with a compound of formula:

where Ar′ is aryl or heteroaryl, where each aryl or heteroaryl isoptionally substituted with one or more substituents independentlyselected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl,halogen, haloalkyl, cyano, nitro, and —NR^(a′)R^(b′), where R^(a′) andR^(b′) are each independently selected from the group consisting ofhydrogen, C₁₋₉alkyl, and C₁₋₉alkylcarbonyl, to form a compound ofFormula I, wherein R¹ is aryl or heteroaryl, where each aryl orheteroaryl is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, halogen, haloalkyl, cyano, nitro, and —NR^(a′)R^(b′),where R^(a′) and R^(b′) are each independently selected from the groupconsisting of hydrogen, C₁₋₉alkyl, and C₁₋₉alkylcarbonyl.
 71. A compoundof formula I according to claim 2, which compounds are selected from thegroup consisting of:4-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-ol;4-[2-methyl-8-(2,4,6-trimethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,8-triazaazulen-3-yl]heptan-4-ol;7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine;2-methyl-3-(1-propylbut-1-enyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine;7-(2,4-dichlorophenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine;7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine;2-methyl-3-(1-propylbutyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine;2-methyl-3-(1-thiophen-2-ylbutyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine;[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]-pyridin-3-yl]dipropylamine;[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]-pyridin-3-yl](1-propylbutyl)amine;[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-furan-2-ylmethyl-propyl-amine;[7-(2-chloro-4,6-dimethyl-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propyl-(3,4,5-trimethoxy-benzyl)-amine;cyclopropylmethyl-(2-methoxyethyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amine;ethyl-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]-pyridin-3-yl]-propylamine;[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-dipropylamine;(1-ethylpropyl)-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amine;7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicacid cyclopropylmethylpropylamide;(3,4-dihydro-1H-isoquinolin-2-yl)-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-methanone;7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine;dimethyl-{4-methyl-5-[2-methyl-3-(1-propylbutoxy)-2,4,5,6-tetrahydro-pyrazolo[3,4-b]pyridin-7-yl]-pyridin-2-yl}-amine;and,2-methyl-3-(2-trifluoromethylphenyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine.